NIE 2023 | Intelligent Future by Wang Junqi: An Integrated Innovation Solution for Exhaled Molecule Analysis Technology and Clinical Application

Exhalation is another form of 'blood', as it, like blood, contains many molecules waiting to be explored and discovered. For example, a large number of inorganic molecules found in exhaled air have been used clinically for diagnosing diseases such as Helicobacter pylori detection, asthma, and monitoring the growth of digestive tract microorganisms. At the same time, there are also many organic molecules in exhaled air, such as acetone, isoprene, n-hexane, etc. Compared to the aforementioned inorganic molecules, organic molecules are more diverse and less abundant, thus requiring more sensitive technologies to keep up. In addition, Dr. Wang Junqi pointed out that exhaled air also contains viruses, bacteria, DNA, RNA nucleic acids, and proteins, and the clinical and research progress in large molecule analysis of exhaled air is advancing rapidly.

Exhaled metabolomics, as a new field in metabolomics, mainly focuses on the qualitative and quantitative analysis of organic compounds in exhaled gases. Dr. Wang Junqi stated that his goals are twofold. The first is to find associations between organic molecule molecules and diseases, followed by discovering disease treatment mechanisms and overall metabolic pathways through the analysis of these organic molecules. To date, underlying metabolic pathways and processes related to diseases that have been identified include oxidative stress responses, coenzyme-induced peroxidation reactions, as well as normal metabolic pathways such as carbohydrate metabolism, lipid metabolism, and amino acid metabolism. Abnormalities in metabolic pathways ultimately lead to changes in organic molecule molecules in exhaled gases, manifested as the emergence of new organic molecules or changes in the content of existing organic molecules. This is also the fundamental principle behind using exhaled gas molecules for disease diagnosis and screening.

Regarding the research progress in exhaled metabolomics, Dr. Wang Junqi pointed out that, from the perspective of research literature output, the number of studies analyzing exhaled VOC molecules has shown a significant increase in recent years, especially with a more rapid growth in recent years. In terms of global pipeline analysis, European and American countries remain leaders in the field of exhaled metabolomics. In terms of disease pipeline analysis, the focus is mainly on respiratory and digestive tract diseases, such as lung cancer, asthma, acute pancreatitis, and tuberculosis.

Regarding the discovery to clinical application of biomarkers, Dr. Wang Junqi believes it can be divided into four steps. The first step involves the mining of biomarkers in exhaled gases, followed by the development of analytical methods and technologies for these biomarkers. The first step involves many unknown factors, thus requiring a general-purpose technical analysis platform such as gas chromatography and mass spectrometry. In the second step, it is necessary to develop clinical analysis methods suitable for specific biomarkers based on clear targets, determine relevant instruments and parameters, and then clinically verify the effectiveness of these methods. Finally, they are submitted to the relevant departments for approval.

Dr. Wang Junqi first introduced the TD-GC-MS technology, which is a platform formed by integrating multiple technologies and includes three key components. First, an exhalation VOC collector named 'ReCIVA' developed by Owlstone Medical is used to capture organic molecules in exhaled samples. In the second part, a thermal desorption device developed by Marks International is introduced to analyze the captured organic molecules. Subsequently, the VOC molecules are separated, quantitatively analyzed, and identified by a GC-MS gas chromatography-mass spectrometer developed by Thermo Fisher. The operation of the entire system requires 10 minutes of sampling, 15 minutes of thermal desorption, and nearly 1.5 hours of molecular analysis. To date, this VOC biomarker mining platform, composed of three key core components, is one of the most advanced technologies in the field of biomarker mining, capable of increasing the sensitivity of gas molecules to PPT levels.

Secondly, Dr. Wang Junqi shared portable PC-GC-MS technology. He stated that the technology has undergone some engineering improvements based on TD-GC-MS technology, and the COVID-19 Breathalyzer using this technology has significantly reduced sampling time. For the novel coronavirus, the device demonstrated 91% sensitivity and 99.3% specificity. Overall, this device is positioned between the VOC biomarker mining platform and the clinical end, and is considered a transitional product that is relatively complex to operate, involving data processing.

Next, Dr. Wang Junqi shared the PTR-TOF-Q-MS technology. This technology includes ion emitters and electron emitters that bombard water and ammonia with electrons, converting water molecules into water vapor and hydrogen ions or ammonium ions, which have relatively high energy. When they encounter VOC molecules in exhaled gas, they can ionize the VOC molecules, followed by mass spectrometry analysis. According to relevant data, devices using this technology can control sampling and analysis time within one minute, with instrument sensitivity reaching 30 PPT. For the novel coronavirus, its sensitivity and specificity have reached 85.7% and 97%, respectively.

Finally, Dr. Wang Junqi shared electronic nose technology. He pointed out that the working principle of the electronic nose originates from bionics. Although there are currently a small number of artificially developed electronic noses and the development is quite challenging. However, if there can be found a sufficient combination of highly specific sensors, such as metal nanoparticles, gold nanoparticles, or metal oxides, electronic nose technology still has many advantages and can systematically track a certain disease within a limited range.

By reviewing the development history of computer technology, Dr. Wang Junqi mentioned that, just as the development of 'mainframe computers - desktop computers - laptops - smartphones' has progressed, the goal of Jingzhi Future is to reduce traditional gas chromatography systems that occupy nearly 50 to 100 square meters in size, enabling the technology to leave the laboratory and enter various application scenarios. To date, Jingzhi Future has reduced gas chromatography technology to the size of a desktop computer. At the same time, Jingzhi Future is developing a handheld gas chromatograph similar in size to a mobile phone, thereby promoting gas chromatography technology into home environments and making it possible for everyone to analyze their own breaths.

Dr. Wang Junqi stated that currently, the BreathSequencer instrument developed by Jingzhi Future based on Micro GC technology can perform full-spectrum analysis of exhaled gases at the PPT level through 3 minutes of sampling and 12 minutes of analysis, and present a complete personal respiratory report. Its working principle is based on three core MEMS chips. In the first chip, molecules of exhaled gas are captured, which then enter the second chip where they are split into individual types of organic molecules. Next, they sequentially enter the third sensor chip, where high-energy photons bombard these organic molecules, ionizing them, thereby collecting electrical signals, that is, converting chemical signals into electrical signals. In the clinical setting, through the collection of large samples and the use of AI algorithms to find biomarker combinations between diseased and healthy tissues, various clinical applications can be carried out, including the diagnosis and screening of cancer, chronic diseases, and epidemics such as the novel coronavirus.

Dr. Wang Junqi pointed out that the overall technical route of the micro gas chromatograph is based on core MEMS chips, thereby replacing components in traditional large laboratories, including sampling and thermal desorption, as well as gas chromatography and mass spectrometry instruments for qualitative and quantitative analysis. This technical route reduces the device volume to one-twentieth of its original size, costs are reduced by one-tenth, and at the same time, the analysis speed is increased by 24 times. Its performance has also been verified by third-party international organizations such as SGS.

In addition to developing hardware products suitable for different application scenarios, Jingzhi Future is establishing a global cloud platform for exhaled metabolomics - 'Jingzhi Future Cloud', dedicated to providing one-stop products and foundational solutions. In practical clinical and modeling processes, it is necessary to analyze samples from a large number of patients, including longitudinal analysis as well as complex database analyses across patients, healthy individuals, and disease types. Due to the inability to complete massive data analysis manually and the process of finding biomarker combinations is not precise enough. Therefore, by applying AI technology, it is possible to find disease-related biomarker combinations more efficiently, quickly, and accurately.

"Intelligent Future Cloud" integrates data exploration engineering, feature query engineering based on breath maps, and disease diagnosis models based on clinical data. With the increase in clinical samples, the platform will possess automatic iteration and learning capabilities, continuously optimizing and improving the specificity and sensitivity for certain diseases. Dr. Wang Junqi proposed that in the field of precision medicine, a single omics perspective cannot solve all problems. Therefore, in addition to breath metabolomics, Intelligent Future has also conducted multi-omics data analysis including genomics and proteomics, aiming to achieve more precise diagnosis and screening for diseases.