Domestic microfluidics technology: the first harvest of IVD industry: four enterprises completed billion yuan financing

Original: Wang Chan The birth of microfluidic technology is the R & D personnel's pursuit of automation and efficiency maximization In the late 1950s, Professor Richard Feynman, the Nobel Laureate of physics in the United States, predicted that the manufacturing technology in the future would develop from large to small In 1959, he used semiconductor materials to miniaturize the experimental mechanical system, thus creating the world's first micro electro mechanical system Systems, MEMS), which has become the cornerstone of microfluidic technology in the future In terms of the definition of microfluidics, the real microfluidics technology came out in 1990 Manz and Widmer of Ciba geigy company in Switzerland applied MEMS technology to realize electrophoresis separation on a microchip, which had been required to be completed in capillary before For the first time, micro total analytical system (ì - TAS) was proposed, which is now known as microfluidic chip Manz and Widmer initially tried to improve their analysis ability, but when the concept of microfluidic chip was proposed, researchers soon realized that the reduction of device size would bring many benefits Microfluidics "micro" refers to the miniaturization of experimental instruments and equipment (the size is tens to hundreds of microns), "flow" refers to the experimental object belongs to the fluid (the volume is nanoliter to a liter), "control" represents the control, operation and processing of the fluid on the miniaturized equipment It belongs to a kind of bottom technology, which interweaves the knowledge of chemistry, fluid physics, microelectronics, new materials and other disciplines Theoretically, any experiment involving fluid should have a place for microfluidic technology Microfluidic chip is the downstream application unit of microfluidic technology Through MEMS technology, a micro biochemical analysis system is built on the surface of solid chip, so as to realize the rapid and accurate processing and detection of inorganic ions, organic substances, proteins, nucleic acids and other specific target objects It gathers the key steps of sample processing, biochemical reaction and result detection that need to be carried out in the laboratory on a small chip, so it is also known as the "chip laboratory" in the industry Since Manz and Widmer developed capillary electrophoresis on chip in 1990, the scientific and industrial circles have been involved in the research and development of various microfluidic chips with capillary electrophoresis as the main application object in this new field Two years later, Agilent, Shimadzu, Hitachi and other medical device companies have completed the research and development of corresponding microfluidic products / systems and put them into the market In 1994, Mike Ramsey, a researcher at Oak Ridge National Laboratory in the United States, based on the original research of Manz and Widmer, improved the chip capillary electrophoresis injection method and improved its performance In the same year, the world's first International Conference on micro total analysis system was held in Enschede, the Netherlands, and microfluidic chips came into the public view The next year, caliper Life Sciences, the world's first company specializing in microfluidic chip technology, was founded in Massachusetts Since the birth of the first microfluidic technology company in 1995, microfluidic chips have officially opened the road of commercialization and industrialization The rapid template replication method PDMS of chips and the soft photolithography micro valve / micro pump of chips have been proposed one after another The first commercialized microfluidic chip instrument was jointly launched by Agilent and galiper in 1999 and applied in the field of biological analysis and clinical analysis Microfluidics technology has been developed for ten years in foreign countries It was not formally introduced into China until the beginning of the 21st century With the gradual rise of IVD industry in China, microfluidics has been gradually known in recent years The first shot of microfluidic circuit is lab on a chip Founded in 2001, the journal is dedicated to the collection of microfluidic research articles One year later, China ushered in the first academic conference with the theme of microfluidics, namely the first National Conference on microfluidics held in Beijing, to realize the large-scale integration of microfluidics chips China's research on microfluidics started here Since 2002, a wave of applications for patent products related to microfluidics has gradually emerged in China By 2012, the annual application volume has reached 100, reaching the peak in 2016, and the total number of applications for patent products has exceeded 600 in 2016 With the decrease of patent applications in the following years, the number of patent applications still remains more than 400 every year At the same time, the number of papers published by Chinese scientists in the field of microfluidic technology has ranked second in the world, and the number of applications for patent products related to microfluidic technology is second only to the United States With the in-depth study of microfluidic technology year by year, people also have a more in-depth exploration in microfluidic material selection, process technology and other related fields In terms of microfluidic materials, semiconductor silicon materials are the first choice for microfluidic chips However, due to the continuous expansion of microfluidic application scenarios, silicon materials can not withstand high voltage and can not be compatible with optical detection technology, so they are abandoned Then came the glass microfluidic chip Glass material can achieve good electroosmosis and optical properties, theoretically is the perfect microfluidic chip material, but the glass material is not easy to be etched and etched, the manufacturing process is complex and time-consuming, and the cost is expensive, so it can not be widely used In contrast, polymer materials show their advantages Polymer processing is simple, raw materials are cheap, and it has good insulation, high pressure resistance, thermal stability, biocompatibility, gas permeability, low modulus of elasticity It can be widely used in capillary electrophoresis microchips, biochemical reaction chips, a variety of optical detection systems The organic polymer represented by PDMS has become a popular material for microfluidic chip fabrication In addition, in the aspect of fabrication technology, currently widely used in the fabrication of microfluidic chips are lithography technology, etching technology, molding, hot pressing, LIGA technology, laser ablation technology and soft lithography, and the specific operation will not be described Microfluidic gymnastics vertical technology is the last step of manufacturing Choosing different forces to control the fluid means that microfluidic chips will ultimately present a wide variety At present, the most common is disc microfluidic chip, which was proposed by Professor L James Lee in 1998 (centrifugal microfluidic cd-elisa Technology) In addition to the disk microfluidic chip, other mainstream microfluidic chips include digital microfluidic chip, pipeline continuous flow chip and drip system chip Because of the different application scenarios, the "force" of the control fluid is different, resulting in the morphological differences Digital microfluidic chips are light and thin like paper chips, often driven by external forces such as electromagnetic field; pipeline continuous flow chips are widely used in the field of CTC cells, which can selectively identify and capture specific cells in the blood, and high-throughput screening, usually driven by capillary force; droplet system chips are controlled by discrete micro droplets, which are suitable for digital PCR and second-generation sequencing Isocellular analysis In addition, there is a paper-based microfluidic chip, which uses paper as the substrate instead of silicon, glass, polymer and other materials The driving force mainly depends on the capillary force of the fiber inside the paper With the development of more than ten years, microfluidic technology has been applied in capillary electrophoresis for more than ten years Because of its powerful integration, the microfluidic chip can process a large number of samples in parallel at the same time It has the characteristics of fast analysis, low energy consumption, low pollution and so on It has appeared in biomedical research, drug synthesis screening, environmental monitoring and protection, health quarantine, judicial identification, biological reagent detection and other application scenarios In these applications, microfluidics has a deeper relationship with in vitro diagnosis As early as 2002, since the first academic conference on microfluidics, China has provided tens of millions of yuan of financial support for companies related to research on microfluidics technology every year to promote the development of domestic microfluidics technology On July 28, 2016, the State Council issued the 13th five year plan for national scientific and technological innovation, which clearly stated that "in vitro diagnostic products should break through key technologies such as microfluidic chips and single molecule detection, develop major products such as full-automatic nucleic acid detection system, develop a batch of diagnostic reagents for early diagnosis and accurate treatment of major diseases and high-precision diagnostic products suitable for basic medical institutions " Subsequently, the Ministry of science and Technology issued the 13th five year plan for biotechnology innovation, which explicitly incorporated microfluidic chips into the new generation of biological detection technology, and called it subversive technology The binding of microfluidics and in vitro diagnosis has been certified from the policy level Nearly 90% of domestic companies that develop microfluidics chips apply it to in vitro diagnosis In addition to policy driven, in vitro diagnosis has become the largest part of microfluidic market segment, which is also inseparable from the rapid development of in vitro diagnosis in recent years China's IVD industry has a compound growth rate of 18.7% from 2017 to 2019 In 2018, the IVD market scale will reach 60.4 billion yuan It is estimated that the IVD market scale in 2019 will exceed 70 billion yuan IVD field drives the innovation of bottom layer technology and becomes the first industry of microfluidic technology At present, the field of in vitro diagnosis can be divided into immunodiagnosis, biochemical diagnosis, molecular diagnosis, POCT, blood diagnosis, microbial diagnosis and others according to the proportion of market segments According to the characteristics of microfluidic chip, such as miniaturization, high efficiency, low cost, etc., the proportion of enabling POCT industry is the largest in IVD sub circuit, the demand of POCT diagnostic equipment for microfluidic chip is also increasing, POCT will become the biggest driving force for the development of microfluidic industry According to the latest statistics of yole analysts, in 2019, the global market scale of microfluidic products will reach 9.98 billion US dollars, and the market of microfluidic equipment will reach 3.48 billion US dollars From 2019 to 2024, the market of microfluidic products will have a compound annual growth rate of 11.7%, and the market of microfluidic products will have a compound annual growth rate of 10.8% It is estimated that in 2024, the market of microfluidic products will reach 17.38 billion US dollars, and the market of microfluidic products will have a compound annual growth rate of 11.7% The equipment market will reach US $5.81 billion In the face of such a large market, capital will certainly not be missed Arterial network has investigated nearly 50 domestic enterprises involved in research and development of microfluidic technology, and counted the number and rounds of financing they have obtained since 2015 Since 2016, on average, more than 10 financing investments have been made to enterprises related to microfluidic technology every year, most of which are in the vicinity of round a (including pre-A and round a +) In 2019, the harvest of microfluidics technology is coming Four in vitro diagnostic enterprises involving microfluidics technology have completed financing of about RMB 100 million, including Rongzhi biology, jingquasi medical, xingeyuan biology and Lanyu biology Among them, quanplex, the "microfluidic nucleic acid quantitative analysis platform" of Rongzhi biology, is a microfluidic gene detection platform based on fluorescence quantitative PCR technology, which has developed three detection applications, namely, quanplex rapid identification system for foodborne pathogens, quanplex avian influenza virus detection system and quanplex respiratory pathogen detection system; Jingzhun medical mainly focuses on molecular diagnosis in the field of IVD, and has established six molecular diagnosis technology platforms, namely real-time fluorescent quantitative PCR, the first generation Sanger sequencing, the second generation high-throughput ngs sequencing, the fluorescence in situ hybridization and microfluidic chip based on capillary electrophoresis fragment analysis,