On April 8, Zhejiang University announced that Professor Zhang Hong of the Institute of verification medicine and molecular imaging has successfully developed the first set of PET molecular image probe microfluidic modular integrated synthesis system with independent intellectual property rights in China.

At present, the developed prototype has the characteristics of low cost, multi module, fast synthesis, automation, etc. different PET molecular image probes can be synthesized on one instrument by adopting the modular strategy of microfluidic chip. The research results of molecular image probe synthesis not only greatly expand the clinical application of individualized and precision medical pet, but also play an important supporting role in the research and development of related new drugs, which is of great strategic significance for China to seize the commanding point of scientific research in this field.

The reporter saw the "little guy" at the scene, a black box with the shape of 35cm × 25cm × 28cm, and equipped with an external display, weighing 7-8kg.

Over the past 12 years, the team has broken through several major technical problems, such as the manufacturing process of highly reliable organic reaction microfluidic chip, multi-channel reagent injection and product extraction, the interface of zero dead volume micro unit, and the integration of gas-liquid fluid control system, electronic control system, reaction control system, software control system, etc., forming 9 important patents, and in terms of radiation amount, preparation time In terms of key energy consumption indexes such as front volume, solvent consumption, power consumption and equipment cost, it is 62% to 98% lower than the existing equipment.

Pet probe, one key, one lock

Positron Emission Tomography is the most advanced molecular imaging technology in the world, which can reflect the changes of cell or molecular level in vivo, and help to understand the biological behavior and characteristics of these specific molecules. Through the specific labeled drugs, it can dynamically display the biochemical changes, gene expression, receptor function and other vital information of various tissues and organs and cell metabolism in the body, reveal the biological process of the disease, and realize the accurate diagnosis and treatment of major diseases such as tumor, cardiovascular and neuropsychiatric diseases.

Molecular image probe is the key of pet and nuclear medicine, and it is a special imaging agent, in which radionuclide plays the role of signal. These radionuclides act as "scouts" to locate the focus for doctors and researchers. But "scouts" can't patrol in human body. They need to hide in a specific medium like Trojan horse. By combining with specific receptors on the lesions, they release signals all the way to leave clues and make biological characteristics.

For example, tumor cells need to consume a lot of glucose, just like a "king of the stomach" who constantly eats food, and normal cells will stop when they are full, so researchers can analyze the focus by storing the nuclide fluorine 18 (18F) in glucose.

Just like to observe tumor cells, 18F is needed. The particularity of PET molecular image probe lies in "one key, one lock". To observe specific biochemical process, a specific probe is needed. At present, there are more than 100 kinds of such molecular image probes in the world. With the continuous exploration of researchers, the number will continue to increase.

However, the existing synthesis method of molecular image probe lags behind the speed of clinical application and research seriously, and it is not competent for the research and development of new PET molecular image probe, and it relies on foreign imports for a long time. There are two disadvantages: one is single function. The preparation methods of each kind of molecular image probe are different, and they have very high requirements for chemical synthesis process. A synthetic instrument can only produce one kind of probe. Second, the synthetic dose is large. It is manifested in the large volume of reaction equipment, the loss of reagents, the large dose of primary synthesis, the waste and low efficiency. "Many of the materials used to make molecular image probes are more expensive than the same weight of gold." According to Zhang Hong, waste can be seen everywhere in synthesis, either in the residual reaction pipeline or in each time the production is greater than the consumption.

In order to give full play to the role of PET molecular image, it is necessary to have a PET molecular image probe synthesizer which is suitable for the individualized clinical application and the individualized scientific research needs. It is urgent for clinical practice to develop a new generation of PET molecular image probe synthesis system.

Overcome bottleneck and condense scientific problems

It is said that if a worker wants to do good things, he must first sharpen his tools. Tian Mei, a member of the research group and deputy director of Zhejiang University Medical Center, introduced that in this study, she first proposed clinical needs, condensed scientific issues, and then conducted cross research with the research team.

The reason why it should be small is that the amount of molecular image probe used each time is very small, which is usually equivalent to the near nanomolar level, i.e. the mass of 10 to the negative 9th power.

"With the successful development of miniaturization in the future, the synthetic equipment can become a mobile platform, or a truck can be installed to see patients." Tian Mei said that all kinds of diseases will cause human body to show flaws. Scientists have found flaws, and their mission is to solve them. PET molecular image probe with small dose and various kinds is urgently needed in clinical and scientific research institutes.

How to do well is to solve the problem of probe preparation.

This is mainly reflected in the fact that the core of the probe is constructed as a radioactive element with short half-life, which can not be purchased and stored as a commodity. Therefore, when PET imaging inspection is carried out, it is necessary to synthesize and prepare PET molecular image probe at the production site of radionuclide as soon as possible, and use it in the near future within a limited time.

Another reason is how to label other media, which requires a special radiochemical synthesis method. The preparation of rapid ultra micro synthesis requires high technology, equipment and automatic control, and the whole process requires the synthesis and purification time to be as short as possible.

Specifically speaking, it is to realize efficient heat and mass transfer and efficient mixing while heating and pressurizing the closed microchannel, as well as rapid drying and phase exchange in the microchannel.

Therefore, Zhang Hong, director of the Institute of medicine and molecular imaging of Zhejiang University, led Tian Mei, pan Jianzhang, special associate researcher of the Department of chemistry of Zhejiang University, long Qun, associate professor of the Institute of microanalysis system of the Department of chemistry, Lei Ming, associate professor of the Department of Chemistry, Xu Guangming, associate professor of the Department of chemistry, special researcher of the school of chemical engineering and bioengineering and Qinggang, focusing on the national health and health major challenges Aiming at the key problems of accurate diagnosis and treatment of major diseases, an interdisciplinary team was established, and the design idea of PET molecular image probe microfluidic modular integrated synthesis system was proposed.

Microfluidic, chemical synthesis in a "hair wire"

When it comes to chemical synthesis, the first thing you think about is the experimental vessels of bottles and cans. Microfluidic technology is to put bottles and cans into the microchannel network of microfluidic chips, in which different fluids can be mixed, reacted and purified. Zhang Hong's team designed a special microfluidic chip, which is made of quartz and is the size of two business cards, but there is much in it.

Microfluidic synthesis is a new micro fast synthesis technology, which can realize the synthesis reaction by controlling the reactant fluid in the chip structure with micro scale channel network. "Small is to solve the problem of fast reaction and micro probe synthesis." According to pan Jianzhang, their microfluidic chip structure makes it at least micron level in one dimension in the effective structure (including channels, reaction chambers and other functional components) to contain fluid.

"Generally, the width and depth of microchannels are 10-500 microns, and the length is 10-100 cm. The smallest channel inner diameter is thinner than a hair thread." Pan said.

Microfluidic technology can significantly increase the area to volume ratio of fluid environment, enhance mass transfer and heat transfer effects, improve reaction selectivity, speed and operation safety, and achieve efficient reaction synthesis. In order to solve the problems of active mixing, rapid drying and equivalence in microfluidic system, the research team solved the problems one by one through the unique microfluidic chip design.

With the deepening of the research, the research team will iterate the microfluidic chip into a microfluidic chip reactor based synthesis system, which includes micropump, micro reservoir, micro tube, micro mixer and differential separation purification column.

After microfluidic chip reactor, taking the preparation of 18F molecular image probe as an example, the enrichment rate of the former channel is more than 400%, and the purification rate of the latter channel is 90%, which greatly improves the production efficiency. The modular system can control the chemical purity and radiochemical purity of PET molecular image probe on-line, which is easy to be popularized and applied in hospitals and research institutions in China, and has good industrialization and market demand.

Modular, easy to synthesize different molecular image probes like changing tapes

The microfluidic chip reactor developed by Zhang Hong's team can synthesize different molecular probes. According to the needs of different probes, they have developed different microfluidic chip reactors. At the same time, different reagents are introduced into the reaction chip through automatic channel switching.

Therefore, once the chip is inserted into the instrument, what reagents are needed, just like selecting drinks on the beverage machine and docking according to the needs. In this way, different molecular image probes can be manufactured by replacing microfluidic chips. Each chip is like a tape. Different tapes can play different songs, and different chips can get different probes.

Zhang Hong's team also built the host control system of the microfluidic synthesizer through systematic integration research, realizing full-automatic remote control. It only needs to choose the configuration scheme on the computer to synthesize the required molecular image probes with one click.

The major scientific and technological achievements are mainly completed by: pet center of Zhejiang University, nuclear medicine discipline of the Second Affiliated Hospital of Zhejiang University Medical College, Institute of nuclear medicine and molecular imaging of Zhejiang University, Key Laboratory of medical molecular imaging of Zhejiang Province, Institute of microanalysis system of Department of chemistry of Zhejiang University, Institute of organic and pharmaceutical chemistry of Department of chemistry of Zhejiang University.

The relevant scientific research work is supported by the national science and technology support plan and the National Foundation Committee's basic research project on scientific instruments.