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The Development History of High Resolution Mass Spectrometry Mass Analyzer

2023/08/24

Mass spectrometry and the Nobel Prize

Mass spectrometry has gone through a century since its birth in the early 20s. In 1906, British physicist Joseph J Thompson won the Nobel Prize in Physics for his work on anode rays, that is, electrons, and his research also laid the foundation for mass spectrometry, and J.J. Thompson is considered by many to be the father of mass spectrometry.

British scientist Francis William Aston, with the help of mass spectrometry designed by him, discovered the existence of isotopes and elucidated the integer rule of isotopes, and won the 1922 Nobel Prize in Chemistry. His work also laid the foundation for the future development of atomic energy science.

German physicists Wolfgang Paul and Hans G. Demelt won the 1989 Nobel Prize in Physics for their invention of ion trap technology, which uses charged quadrupole to trap ions, in the fifties.

American analytical chemist John B. Fenn and Japanese scientist Koichi Tanaka shared the 2002 Nobel Prize in Chemistry for their contributions to the development of electrospray and MALDI ionization techniques, respectively. These two technologies have greatly expanded the application range of mass spectrometry and liquid phase combination, and directly promoted the research of biological macromolecules.

Various new mass spectrometry techniques have been introduced and the range of applications has been expanded, becoming one of the most important tools for scientific research, and thirteen Nobel Prizes have been awarded related to mass spectrometry.

The birth of quadruple mass spectrometry

Based on the quadrupole theory of German physicist Wolfgang Paul, in 1964, the scientific instrument department of the American company Electronics Associates Inc (EAI, which at that time mainly served NASA's space program) company launched a successful quadrupole mass spectrometry product Quad 200 for residual gas analyzers. In 1971, Hewlett Packard introduced its first quadrupole GC/MS system for a wide range of applications in petrochemistry, organic synthesis, analytical chemistry and life sciences. Nowadays, quadrupole mass spectrometry has become a relatively mature technology for mixture separation and detection, and domestic instrument manufacturers mainly focus on the development of this field, such as Hexin Instrument (688622. SH), Concentrated Light Technology (300203.SZ).

Quadrupole mass spectrometry hardware diagram

Introduction to high-resolution mass spectrometry

The industry usually refers to mass spectrometry with a resolution above 10000 (FWHM) as high-resolution mass spectrometry, mainly including bifocal magnetic mass spectrometry, time-of-flight mass spectrometry, orbital well mass spectrometry and Fourier transform ion cyclotron resonance mass spectrometry. In the field of high-resolution mass spectrometry, the most successful products for commercial application are Thermo's Orbitrap orbital well mass spectrometry series and Agilent, Waters, Bruker's time-of-flight mass spectrometry series, and few domestic manufacturers are involved.

(1) Time-of-flight mass spectrometry (TOF).

Time-of-flight mass spectrometry germinated in the Manhattan Project, as early as 1942-1945, scientists separated uranium with an abundance of only 0.72% from the natural isotope uranium by preparative mass spectrometry 235, and in 1952, with the publication of the TOF patent, the advantages of time-of-flight mass spectrometry in two very important performance: parameter sensitivity and resolution compared to traditional magnetic mass spectrometry are obvious. However, the dispersed ion energy and spatial position limit the time-of-flight mass spectrometry to improve the resolution, and it is difficult to apply it in life science research. Focusing the initial space position and energy around efficient and high-tech has become an urgent problem for instrument manufacturers, and different instrument companies have designed to increase the length of the flight tube or the number of reflections to improve the resolution of the instrument, such as Agilent, Bruker and Waters.

布鲁克的TOF系列（通过增加飞行管长度增加分辨率）

（2）Orbitrap轨道阱系列

受困于传统TOF的离子损失和分辨率，1981年，有个叫Knight的科学家提出了一个改进的设计：把外环电极分割成左右两段，形状也从圆环形变成纺锤形，称之为“Knight trap”。

1999年，英国曼彻斯特 HD Technologies 公司的Makarov团队在“Knight trap”的基础上，结合自己TOF多年研究经验，在当年的ASMS上首次公开轨道阱Orbitrap技术（Orbital轨道+trap阱），2000年，HD Technologies 公司被Thermo收购，这个硬币大小的质量分析器改变当今质谱格局（足以获得诺奖）。不同于TOF无限增加飞行管的长度或者反射次数，轨道阱技术是利用磁场把离子如同卫星一样约束在一定轨道范围内做圆周运动，通过释加外部变频电压，离子在阱内左右震荡，随着时间延长，不同离子得以区分开。Orbitrap诞生20多年以来，没有新的质量分析器被研究出来，围绕Orbitrap开发出来的质谱系列Q Exactive HF-X和Q Exactive HF统治了高端质谱应用十多年。

Orbitrap构造

（3）timsTOF PRO的诞生

Orbitrap是21世纪初质谱界的礼物，Thermo也将其拓展到各个领域的应用，环境诊断、疾病早筛、抗体药物分析、代谢组学研究、蛋白组学研究等等领域。但应用于生物大分子检测却逐渐暴露出的问题，蛋白组学需要在短时间类需要检测数十万多条多肽，Orbitrap提升分辨率的同时无疑牺牲了扫描速度（离子运行时间越久分辨率越高），Mann等在2011年指出最大的损失来自于对大量低强度信号的舍弃，只有约16%的intensity较大的多肽母离子会被碎裂得到二级谱图，而这其中能够成功解谱的约占一半。如何提高扫描速度去提高多肽的鉴定效率？被遗忘的TOF被拾了起来（不受扫描速度的限制），2017年Mann的团队和Bruker工程师在TOF的基础上进行了改进，创新性的将tims淌度技术应用在TOF前端，在不牺牲扫描速度的同时，提高的离子的聚集度以及横截面积（CCS）的分离。自此，高端质谱行业由Thermo的一家独大变成了与Bruker的分庭抗礼。

timsTOF PRO 硬件示意图

timsTOF pro 和 Orbitrap参数比较

MS	Exploris 480	timsTOF Pro
Scan rate	Up to 40 Hz	>120 Hz
Resolution	Up to 480K	Up to 50K
Quad isolation	Down to 0.4au	Down to 1 au
Mass range	40-6000m/z	20-40000m/z
Dissociation	HCD	CID
Detector	Orbitrap	TOF

高分辨质谱的市场规模

据统计，2021年Thermo Fisher Scientific's Life Sciences部门实现11.2亿美元收入，其中包括质谱和相应试剂耗材，Bruker BDAL部门实现2.2亿美元收入，主要来自timsTOF Pro及液相收入,Waters质谱部门实现1.8亿美元收入，Agilent质谱部门实现3.8亿美元收入。随着Thermo的Orbitrap专利即将到期，国外各个公司也在围绕Orbitrap质量分析器开发新一代产品。

质谱发展百年已形成了多学科交叉，融合了理论物理、工程学、电子科学、生命科学等多领域学科。国内质谱目前主要以三重四极杆和离子阱为主，国内受困于基础物理理论及工业模具、芯片、精密加工、变频装置、机械泵和分子泵、工业软件等软硬件发展桎梏，以及国外技术封锁及质谱领域专业人员的缺失，导致飞行时间质谱和轨道阱国内尚未得到发展，难以形成技术体系。纵观质谱应用史，质谱每一次进步创新，都是由需求端提出问题，科学家及仪器厂商合作进行改造，对于国内质谱的发展具有很好的借鉴意义。

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