Sensory SystemsSensory SystemsСенсорные системы0235-00923034-5936The Russian Academy of Sciences69675110.7868/S3034593625030036ОБЗОРЫResearch ArticleDisease detection by volatile organic compound analysis: II. Direct sample injection mass spectrometryОбнаружение заболеваний по анализу летучих органических соединений: II. Масс-спектрометрия с прямым вводом пробыNikiforovS. M.НикифоровС. М.PentoA. V.ПентоА. В.KiryukhinaO. O.КирюхинаО. О.RodionovaE. I.РодионоваЕ. И.a.rodionova@gmail.comInstitute of General Physics of the Russian Academy of SciencesИнститут общей физики им. А.М. Прохорова Российской академии наукFederal State Budgetary Institution of Science Institute for Information Transmission Problems named after A.A. Kharkevich RASФедеральное государственное бюджетное учреждение науки Институт проблем передачи информации им. А.А. Харкевича РАН15122025393VOL 39, NO3 (2025)ТОМ 39, №3 (2025)253721112025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0235-0092/article/view/696751

The results of the application of mass spectrometry with direct sample injection in the diagnosis of diseases in humans and laboratory animals are presented. Various methods for obtaining mass spectra of volatile organic compounds (VOCs) are considered, allowing VOCs analysis without using sample concentration and chromatographic separation. This approach, reminiscent of the work of trained sniffing dogs, ensures minimal sample analysis time and high sensitivity, which is extremely important for mass analysis. The authors’ own results on the development of a new method of VOC ionization for the analysis of biological samples are also presented.

В обзоре представлены результаты применения метода масс-спектрометрии с прямым вводом пробы в диагностике заболеваний человека и лабораторных животных. Рассмотрены различные способы получения масс-спектров летучих органических соединений (ЛОС), обеспечивающие возможность анализа ЛОС без применения концентрации пробы и хроматографического разделения. Такой подход, напоминающий работу собак-детекторов, обеспечивает минимальное время анализа пробы и высокую чувствительность, что исключительно важно для массового анализа. В обзор, в том числе, включены собственные результаты авторов по разработке нового способа ионизации ЛОС для применения в анализе биологических проб.

mass spectrometryvolatile organic compoundsdiagnosis of diseasesмасс-спектрометриялетучие органические соединениядиагностика заболеванийРабота выполнена без внешнего финансирования.Тальрозе В.Л., Любимова А.К. Вторичные процессы в ионном источнике масс-спектрометра. ДАН СССР. 1952. Т. 86. С. 909-912.Black G., Lowe C., Anumol T., Bade J., Favela K., Feng Y. L., Knolhoff A., Mceachran A., Nuñez J., Fisher C., Peter K., Quinete N.S., Sobus J., Sussman E., Watson W., Wickramasekara S., Williams A., Young T. Exploring chemical space in non-targeted analysis: a proposed ChemSpace tool. Anal. Bioanal. Chem. 2023. V. 415 (1). P. 35-44. https://doi.org/10.1007/s00216-022-04434-4Blake R.S., Monks P.S., Ellis A.M. Proton-transfer reaction mass spectrometry. Chem. Rev. 2009. V. 109 (3). P. 861-896. https://doi: 10.1021/cr800364qBlanco F.G., Vidal-de-Miguel G. Breath analysis by secondary electro-spray ionization-mass spectrometry to interrogate biologically significant metabolites non-invasively. Crit. Rev. Anal. Chem. 2023. V. 53 (4). P. 825-837. https://doi: 10.1080/10408347.2021.1981226Broza Y.Y., Mochalski P., Ruzsanyi V., Amann A., Haick H. Hybrid volatolomics and disease detection. Angew Chem. Int. Ed. Engl. 2015. V. 54 (38). P. 11036-11048. https://doi: 10.1002/anie.201500153.Bukharina A.B., Pento A.V., Simanovsky Y.O., Nikiforov S. M. Mass spectrometry of volatile organic compounds ionised by laser plasma radiation. Quantum Electronics. 2021. V. 51(5). P. 393. https://doi.org/10.1016/j.ijms.2020.116498Bukharina A.B., Fedulkina A.O., Demidova K.N., Pento A.V., Maltseva L.D., Simanovsky Y.O., Nikiforov S.M., Morozova O.L. Omics technologies in screening for kidney disease in children with congenital uropathy. Annals of the Russian academy of medical sciences. V. 77 (5). P. 354-361. https://doi: 10.15690/vramn2107Chen H., Venter A., Cooks R.G. Extractive electrospray ionization for direct analysis of undiluted urine, milk and other complex mixtures without sample preparation. Chem. Commun. 2006. V. 19. P. 2042-2044. https://doi: 10.1039/b602614a.Choueiry F., Zhu J. Secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) fingerprinting enabled treatment monitoring of pulmonary carcinoma cells in real time. Anal. Chim. Acta. 2022. V. 1189. P. 339230. https://doi: 10.1016/j.aca.2021.339230.Eliuk S., Makarov A. Evolution of orbitrap mass spectrometry instrumentation. Annu. Rev. Anal. Chem. V. 8 (5). P. 61-80. https://doi: 10.1146/annurev-anchem-071114-040325.Filatov V.V., Nikiforov S.M., Zelenov V.V., Pento A.V., Bukharina A.B., Sulimenkov I.V., Brusov V.S., Yu J., Kozlovskiy V.I. Ionization of organic molecules with metal ions formed in the laser plasma. J. Mass Spectrom. V. 56 (5). P. e4723. https://doi: 10.1002/jms.4723.Fu L., Wang L., Wang H., Yang M., Yang Q., Lin Y., Guan S., Deng Y., Liu L., Li Q., He M., Zhang P., Chen H., Deng G. A cross-sectional study: a breathomics based pulmonary tuberculosis detection method. BMC Infect. Dis. 2023. V. 23 (1). P. 148. https://doi: 10.1186/s12879-023-08112-3.He J., Sinues P. L., Hollmén M., Li X., Detmar M., Zenobi R. Fingerprinting breast cancer vs. normal mammary cells by mass spectrometric analysis of volatiles. Sci. Rep. 2014. V. 4. P. 5196. https://doi: 10.1038/srep05196.Herth J., Schmidt F., Basler S., Sievi N.A., Kohler M. Exhaled breath analysis in patients with potentially curative lung cancer undergoing surgery: a longitudinal study. J. Breath Res. 2024. V. 18 (3). P. 036003. https://doi: 10.1088/1752-7163/ad48a9.Huang Q., Wang S., Li Q., Wang P., Li J., Meng S., Li H., Wu H., Qi Y., Li X., Yang Y., Zhao S., Qiu M. Assessment of Breathomics Testing Using High-Pressure Photon Ionization Time-of-Flight Mass Spectrometry to Detect Esophageal Cancer. JAMA Netw Open. 2021. V. 4 (10). P. e2127042. https://doi: 10.1001/jamanetworkopen.2021.27042.Jansson B.O., Larsson B.T. Analysis of organic compounds in human breath by gas chromatography-mass spectrometry. J. Lab. Clin. Med. 1969. V. 74 (6). P. 961-966.Jiao B., Zhang S., Bei Y., Bu G., Yuan L., Zhu Y., Yang Q., Xu T., Zhou L., Liu Q., Ouyang Z., Yang X., Feng Y., Tang B., Chen H., Shen L. A detection model for cognitive dysfunction based on volatile organic compounds from a large Chinese community cohort. A&D. 2023. V. 19 (11). P. 4852-4862. https://doi: 10.1002/alz.13053.Krilaviciute A., Heiss J. A., Leja M., Kupcinskas J., Haick H., Brenner H. Detection of cancer through exhaled breath: a systematic review. Oncotarget. 2015. V. 6 (36). P. 38643. https://doi: 10.18632/oncotarget.5938.Krotoszynski B., Gabriel G., O’Neill H., Claudlo M. P. A. Characterization of human expired air: a promising investigative and diagnostic technique. J. Chromatogr. Sci. 1977. V. 15 (7). P. 239-244. https://doi: 10.1093/chromsci/15.7.239.Kwak J., Willse A., Preti G., Yamazaki K., Beauchamp G.K. In search of the chemical basis for MHC odourtypes. Proc. Biol. Sci. 2010. V. 277. P. 2417–2425. https://doi: 10.1098/rspb.2010.0162.Lagg A., Taucher J., Hansel A., Lindinger, W. Applications of proton transfer reactions to gas analysis. Int. J. Mass Spectrom. Ion Processes. 1994. V. 134 (1). P. 55-66. https://doi: 10.1016/0168-1176(94)03965-8Law W. S., Wang R., Hu B., Berchtold C., Meier L., Chen H., Zenobi, R. On the mechanism of extractive electrospray ionization. Anal. Chem. 2010. V. 82 (11). P. 4494-4500. https://doi: 10.1021/ac100390t.Leemans M., Bauër P., Cuzuel V., Audureau E., Fromantin I. Volatile organic compounds analysis as a potential novel screening tool for breast cancer: A systematic review. Biomark. Insights. 2022. V. 17. P. 11772719221100709. https://doi: 10.1177/11772719221100709.Li L., Chen H., Shi J., Chai S., Yan L., Meng D., Cai Z., Guan J., Xin Y., Zhang X., Sun W., Lu X., He M., Li Q., Yan X. Exhaled breath analysis for the discrimination of asthma and chronic obstructive pulmonary disease. J. Breath Res. 2024. V. 18 (4). P. 046002. https://doi: 10.1088/1752-7163/ad53f8.Liu J., Chen H., Li Y., Fang Y., Gu Y., Li S., Xu J., Jia Z., Zou J., Liu G., Xu H., Wang T., Wang D., Jiang Y., Wang Y., Tang X., Qiao G., Zhou Y., Bai L., Zhou R., Lu C., Wen H., Li J., Huang Y., Zhang S., Feng Y., Chen H., Xu S., Zhang B., Liu Z., Wang X. A novel non-invasive exhaled breath biopsy for the diagnosis and screening of breast cancer. J. Hematol. Oncol. 2023. V. 16 (1). P. 63. https://doi: 10.1186/s13045-023-01459-9.Martínez-Lozano P., Rus J., Fernández de la Mora G., Hernández M., Fernández de la Mora J. Secondary electrospray ionization (SESI) of ambient vapors for explosive detection at concentrations below parts per trillion. JASMS. 2009. V. 20. P. 287-294. https://doi: 10.1016/j.jasms.2008.10.006.Meng S., Li Q., Zhou Z., Li H., Liu X., Pan S., Li M., Wang L., Guo Y., Qiu M., Wang J. Assessment of an exhaled breath test using high-pressure photon ionization time-of-flight mass spectrometry to detect lung cancer. JAMA Netw. Open. 2021. V. 4 (3). P. e213486. https://doi: 10.1001/jamanetworkopen.2021.3486.Munson M. S. B., Field F. H. Chemical ionization mass spectrometry. I. General introduction. JACS. 1966. V. 88 (12). P. 2621-2630.Raffaelli A., Saba A. Atmospheric pressure photoionization mass spectrometry. Mass Spectrom. Rev. 2023. V. 22 (5). P. 318-331. https://doi: 10.1002/mas.10060.Setchell J.M., Vaglio S., Abbott K.M., Moggi-Cecchi J., Boscaro F., Pieraccini G., Knapp L.A. Odour signals major histocompatibility complex genotype in an Old World monkey. Proc. Biol. Sci. 2011. V. 278. P. 274–280. https://doi: 10.1098/rspb.2010.0571.Sinues P. M. L., Landoni E., Miceli R., Dibari V. F., Dugo M., Agresti R., Tagliabue E., Cristoni S., Orlandi R. Secondary electrospray ionization-mass spectrometry and a novel statistical bioinformatic approach identifies a cancer-related profile in exhaled breath of breast cancer patients: a pilot study. J. Breath Res.2015. V. 9 (3). P. 031001. https://doi: 10.1088/1752-7155/9/3/031001.Španěl P., Dryahina K., Omezzine Gnioua M., Smith D. Different reactivities of H3O+ (H2O) n with unsaturated and saturated aldehydes: ligand-switching reactions govern the quantitative analytical sensitivity of SESI-MS. Rapid Commun. Mass Spectrom. 2023. V. 37 (9). P. e9496. https://doi: 10.1002/rcm.9496.Streckenbach B., Osswald M., Malesevic S., Zenobi R., Kohler M. Validating discriminative signatures for obstructive sleep apnea in exhaled breath. Cells. 2022. V. 11 (19). P. 2982. https://doi: 10.3390/cells11192982.Tsou P.H., Lin Z.L., Pan Y.C., Yang H.C., Chang C.J., Liang S.K., Wen Y.F., Chang C.H., Chang L.Y., Yu K.L., Liu C.J., Keng L.T,. Lee M.R., Ko J.C., Huang G.H., Li Y.K. Exploring volatile organic compounds in breath for high-accuracy prediction of lung cancer. Cancers. 2021. V. 13 (6). P. 1431. https://doi: 10.3390/cancers13061431.Verenchikov A. N., Makarov V. V., Vorobyev A. V., Kirillov S. N. A perspective of multi-reflecting TOF MS. Mass Spectrom. Rev. 2024. https://doi.org/10.1002/mas.21915Wang Y., Jiang J., Hua L., Hou K., Xie Y., Chen P., Liu W., Li Q., Wang S., Li H. High-pressure photon ionization source for TOFMS and its application for online breath analysis. Anal. Chem. 2016. V. 88 (18). P. 9047-9055. https://doi: 10.1021/acs.analchem.6b01707.Wilson D.A., Sullivan R.M. Cortical processing of odor objects. Neuron. 2011. V. 72. P. 506–519. https://doi: 10.1016/j.neuron.2011.10.027.Wu, C., Siems, W. F., & Hill, H. H. (2000). Secondary electrospray ionization ion mobility spectrometry/mass spectrometry of illicit drugs. Analytical chemistry. 72(2), 396-403. https://doi.org/10.1021/ac9907235Wüthrich C., Giannoukos S. Advances in secondary electrospray ionization for breath analysis and volatilomics. Int. J. Mass Spectrom. 2024. V. 498. P. 117213. https://doi: 10.1016/j.ijms.2024.117213Xiang C., Yang H., Zhao Z., Deng F., Lv Y., Yang Y., Duan Y., Li W., Hu B. Volatolomics analysis of exhaled breath and gastric-endoluminal gas for distinguishing early upper gastrointestinal cancer from benign. J. Breath Res. 2023. V. 17 (3). P. 036004. https://doi: 10.1088/1752-7163/accfb8.Yang M., Jiang J., Hua L., Jiang D., Wang Y., Li D., Wang R., Zhang X., Li H. Rapid detection of volatile organic metabolites in urine by high-pressure photoionization mass spectrometry for breast cancer screening: a pilot study. Metabolites 2023. V. 13 (7). P. 870. https://doi: 10.3390/metabo13070870.Yu Z., Liu C., Niu H., Wu M., Gao W., Zhou Z., Huang Z., Li X. Real time analysis of trace volatile organic compounds in ambient air: a comparison between membrane inlet single photon ionization mass spectrometry and proton transfer reaction mass spectrometry. Anal. Methods. 2020. V. 12 (35). P. 4343-4350. https://doi: 10.1039/d0ay01102a.Zhou M., Wang Q., Lu X., Zhang P., Yang R., Chen Y., Xia J., Chen, D. Exhaled breath and urinary volatile organic compounds (VOCs) for cancer diagnoses, and microbial-related VOC metabolic pathway analysis: a systematic review and meta-analysis. Int. J. Surg. 2024. V. 110 (3). P. 1755-1769. https://doi: 10.1097/JS9.0000000000000999.Zhou W., Huang C., Zou X., Lu Y., Shen C., Ding X., Wang H., Jiang H., Chu Y. Exhaled breath online measurement for cervical cancer patients and healthy subjects by proton transfer reaction mass spectrometry. Anal. Bioanal. Chem. 2017. V. 409 (23). P. 5603-5612. https://doi: 10.1007/s00216-017-0498-0.Wu C., Siems W.F. & Hill H.H. (2000). Secondary electrospray ionization ion mobility spectrometry/mass spectrometry of illicit drugs. Analytical chemistry. 72(2), 396-403.Yu Z., Liu C., Niu H., Wu M., Gao W., Zhou Z., Huang Z., Li X. Real time analysis of trace volatile organic compounds in ambient air: a comparison between membrane inlet single photon ionization mass spectrometry and proton transfer reaction mass spectrometry. Anal. Methods. 2020. V. 12 (35). P. 4343-4350. https://doi: 10.1039/d0ay01102a.Zhou M., Wang Q., Lu X., Zhang P., Yang R., Chen Y., Xia J., Chen, D. Exhaled breath and urinary volatile organic compounds (VOCs) for cancer diagnoses, and microbial-related VOC metabolic pathway analysis: a systematic review and meta-analysis. Int. J. Surg. 2024. V. 110 (3). P. 1755-1769. https://doi: 10.1097/JS9.0000000000000999.Zhou W., Huang C., Zou X., Lu Y., Shen C., Ding X., Wang H., Jiang H., Chu Y. Exhaled breath online measurement for cervical cancer patients and healthy subjects by proton transfer reaction mass spectrometry. Anal. Bioanal. Chem. 2017. V. 409 (23). P. 5603-5612. https://doi: 10.1007/s00216-017-0498-0.