Development of a Miniature Mass Spectrometer and Ionization Methods for Direct Small Biomolecule Analysis

Precision medicine is one of the most popular topics in the world. The successful analysis of biomarkers and biomolecules in an accurate and precise way is key for precision medicine. Currently, most developed methods are focused on gene sequencing, proteomics or targeted molecular therapy. Qualitative and quantitative tests of small biomolecules are still lacking in attention. The rapid, direct analysis of small biomolecules with an accessible instrument is highly demanded. This study focuses on mass spectrometry based technologies that seek an easy-to-use and high throughput solution for direct biomolecule analysis. The development of a portable mass spectrometer at Purdue has been underway for more than a decade. The miniature ion trap mass spectrometer can provide in-field analysis capability for a large variety of samples, such as drug molecules, lipids or peptides. Ionization methods such as paper spray, extractive spray and paper-capillary spray have been developed to couple with the miniature mass spectrometer. The advancement of ambient ionization facilitates real-time analysis using Miniature mass spectrometry. Taking advantage from the solid fundamental research done in Purdue, this study focuses on the development of a new miniature mass spectrometer system and new ionization methods for direct quantification of biomolecules. Firstly, a new vacuum design for the miniature mass spectrometer was constructed and tested. Using this new design, a new miniature mass spectrometer, Mini β, was evaluated in detail. Lastly, a new ionization method was developed for the direct analysis of chemicals on surfaces. The vacuum system is one of the most important systems in a mass spectrometer. For the miniature ion trap mass spectrometer developed in Purdue, a discontinuous atmospheric pressure interface (DAPI) is used with a Hipace-10 turbo pump. In this study, a new turbo pump, Hipace-30, is used to improve the pumping speed and analytical performance of the instrument. A dual-linear ion trap system is constructed using the new vacuum design. The pressure variation curve, isolation performance, collision induced dissociation efficiency and the mass selective axial transfer efficiency are studied in detail. The duty cycle of the new system is increased by a factor of three. Using the new turbo pump, a supplementary DAPI can be used to actively control the pressure in the vacuum chamber to a desired value which increases the ion manipulation efficiency. A new miniature mass spectrometer, Mini β, has been designed and constructed based on the new pumping configuration with a dual quadrupole linear ion trap system. The analytical performance of the new system is evaluated in this study. As a linear ion trap mass spectrometer, the Mini β can achieve sub-ppb level of detection limit using nano-ESI and ppb level using paper capillary spray cartridge. Mini β has a resolving power higher than 700 with a scan speed of 1000Da/s and is capable to analyze both positive and negative ions with MSn capability. The new system also demonstrates the possibility of analyzing biomolecules, including lipids, peptides and small proteins. A paper-capillary spray cartridge ion source has been designed to couple the new Mini β instrument. Using the new Mini β mass spectrometer with sample cartridge, the successful detection of illicit drug in urine and illegal additive in medicine has been demonstrated using real samples. For the ionization and sampling method, a sampling probe is designed based on the DAPI system and an internal discharge ionization method has been evaluated. The ionization process is synchronized with the DAPI operation. Non-volatile chemicals with a vapor pressure around 10-4 torr on a surface can be directly analyzed. Sample with lower vapor pressure can still be analyzed by using a 1-watt heater to heat the sample gas. Methanol and water vapor were found to be effective to improve the ionization efficiency for analyte that generates protonated ions. With the advanced vacuum and sample introduction technology, the new miniature mass spectrometer, Mini β, and the new ionization and sampling technology, portable mass spectrometer system can be further implemented into the precision medicine area for clinical applications