A Miniature Orthogonal Injection Ion Funnel (MO-IF) Providing Enhanced Performance for the Miniature Mass Spectrometer.

The sensitivity of the miniature mass spectrometer (mini-MS) is largely restricted by the ion transmission in rough vacuum region. Even though various "in-line" ion transfer devices have improved mini-MS sensitivity, the severe dynamic gas is still weakening the efficiency of ion transmission in this region. Inspired by the "off-axis" ion funnel design in the lab-scale mass spectrometers, a miniature orthogonal injection ion funnel (MO-IF) was developed in this study for the mini-MS with a continuous atmospheric pressure interface. Capable of directing injected ions by 90° and then transport them forward to the downstream skimmer, the MO-IF enabled the separation of ions from the dynamic gas flow jetted out of the inlet capillary. The key factors were optimized for the MO-IF, including the effects of RF amplitude, DC electric fields, and the position of the repeller. Under optimized conditions, the MO-IF minimized the negative effects of dynamic gas and improved the ion transmission efficiency by ∼2-fold in comparison with the in-line injection ion funnel. As a result, a lower limit of detection of 0.5 ng/mL were obtained with good linearity for hypaconitine. Additionally, the MO-IF further decreased the buffer gas pressure in the second vacuum chamber and improved the mass resolution by 1.1-1.5 times at different scan rates.

Swab-in-Capillary Electrospray Ionization and a Miniature Mass Spectrometer for In Situ Drug Analysis.

In situ analysis of drugs has been in increasing demand in many fields. As an updated version of capillary-in-capillary electrospray ionization (CC-ESI) developed previously, a disposable swab-in-capillary electrospray ionization (SC-ESI) source was designed in this study. With a micro medical swab for sampling and an integrated filter membrane for online filtration, SC-ESI was able to directly sample and MS analyze complex samples without the need for pretreatment. Coupled with a miniature mass spectrometer, SC-ESI was applied for direct analysis of effective ingredients in therapeutic drugs (in tablet, capsule, and liquid droplet) and drugs in saliva and quantitation of therapeutic drugs in blood. The limits of detection in absolute amounts were obtained as 1 ng for fentanyl and 0.5 ng for cocaine in saliva. Combining with an internal standard method, SC-ESI acquired linear quantitation ranges of 100-5000 ng/mL for imatinib in whole blood and 100-2000 ng/mL for clozapine in serum with high accuracies and precisions. The entire analysis process, from sampling to data acquisition, can be completed in less than 2 min. As demonstrated as a cheap, portable, and sampling-effective ionization source, SC-ESI has shown great potential for in situ drug analysis, especially in border drug screening and clinical therapeutic drug monitoring.

Miniature mass spectrometers and their potential for clinical point-of-care analysis.

Mass spectrometry (MS) has become a powerful technique for clinical applications with high sensitivity and specificity. Different from conventional MS diagnosis in laboratory, point-of-care (POC) analyses in clinics require mass spectrometers and analytical procedures to be friendly for novice users and applicable for on-site clinical diagnosis. The recent decades have seen the progress in the development of miniature mass spectrometers, providing a promising solution for clinical POC applications. In this review, we report recent advances of miniature mass spectrometers and their exploration in clinical applications, mainly including the rapid analysis of illegal drugs, on-site monitoring of therapeutic drugs, and detection of biomarkers. With improved analytical performance, miniature mass spectrometers are also expected to apply to more and more clinical applications. Some promising POC analyses that can be performed by miniature mass spectrometers in the future are discussed. Lastly, we also provide our perspectives on the challenges in technical development of miniature mass spectrometers for clinical POC analysis.

Deep Bottom-up Proteomics Enabled by the Integration of Liquid-Phase Ion Trap.

In bottom-up proteomics, the complexity of the proteome requires advanced peptide separation and/or fractionation methods to acquire an in-depth understanding of protein profiles. Proposed earlier as a solution-phase ion manipulation device, liquid phase ion traps (LPITs) were used in front of mass spectrometers to accumulate target ions for improved detection sensitivity. In this work, an LPIT-reversed phase liquid chromatography-tandem mass spectrometry (LPIT-RPLC-MS/MS) platform was established for deep bottom-up proteomics. LPIT was used here as a robust and effective method for peptide fractionation, which also shows good reproducibility and sensitivity on both qualitative and quantitative levels. LPIT separates peptides based on their effective charges and hydrodynamic radii, which is orthogonal to that of RPLC. With excellent orthogonality, the integration of LPIT with RPLC-MS/MS could effectively increase the number of peptides and proteins being detected. When HeLa cells were analyzed, peptide and protein coverages were increased by ∼89.2% and 50.3%, respectively. With high efficiency and low cost, this LPIT-based peptide fraction method could potentially be used in routine deep bottom-up proteomics.

Capillary-in-Capillary Electrospray Ionization (CC-ESI) Source Enabling Convenient Sampling and Quantitative Analysis for Point-of-Care Testing.

With outstanding analytical performances, mass spectrometry (MS) has shown great potential for clinical applications. To facilitate the sampling process and quantitative analysis, a capillary-in-capillary electrospray ionization (CC-ESI) source was developed in this study. Utilizing two nested capillaries as a sampler and an ESI emitter, the source enabled spontaneous liquid sampling based on the capillary phenomenon and electrospray ionization mass spectrometry (ESI-MS) analysis. Apart from the cheap price, high portability, and disposability, the CC-ESI had merits of quantitation capability as well as adequate sensitivity. By coupling CC-ESI to a miniature mass spectrometer (mini-MS), a limit of detection (LOD) of 1 ng/mL was achieved for standard imatinib at collision-induced dissociation (CID) tandem MS mode, and a LOQ of 1 ng/mL was obtained for atenolol and imatinib (with isotopic internal standard) at multiple ion reaction monitoring (MRM) modes. As two demonstrations for analysis of practical samples, rapid analysis of abused drugs on surface and quantitative analysis of therapeutic drugs in whole blood were also performed with a CC-ESI mini-MS.

Field-Gradient-Focusing Ion Guide for Enhanced Transfer Efficiency of Low-Mass Ions.

Efficient transmission of low-mass ions in a rough vacuum pressure region has always been a challenging issue in mass spectrometry (MS). In this study, a novel ion guide, namely, field-gradient-focusing ion guide (FGF-IG), was proposed to improve the transfer efficiency of ions, especially low-mass ions in a rough vacuum region. The FGF-IG has 12 electrodes whose surfaces gradually narrowed and tilted inward, and its electric field gradually varies from dodecapole (or multipole) to quadrupole along the ion transfer route. The field radius was gradually decreased from 6 to 2 mm in the multipole region (65 mm in length) and finally remained unchanged as 2 mm in the quadrupole region (20 mm in length). By integrating into a miniature mass spectrometer (mini-MS) with a continuous atmospheric pressure interface, this ion guide was optimized in terms of inlet capillary position, radio frequency amplitude, and direct current voltage applied on it. Results showed that a reduced low-mass discrimination effect and improved efficiency of simultaneously transferring mid and low m/z ions were achieved for FGF-IG compared with a conventional ion funnel. Under optimized conditions, a limit of detection of 1 ng/mL was obtained for both reserpine (m/z 609) and arginine (m/z 175) ions by integrating FGF-IG into the mini-MS. The sensitivity of smaller arginine ions using FGF-IG was enhanced by ∼10 times than that obtained using the conventional ion funnel (10 ng/mL) in comparative experiments. The idea of smooth transfer from dodecapole to quadrupole fields could be extended to other multipole fields, as well as in lab-scale MS instruments.

Coupling handheld liquid microjunction-surface sampling probe (hLMJ-SSP) to the miniature mass spectrometer for automated and in-situ surface analysis.

In-situ surface analysis has always been a significant but challenging issue in many analytical applications. To enable surface sampling and MS analysis on the field, a handheld liquid microjunction-surface sampling probe (hLMJ-SSP) was coupled to a miniature mass spectrometer in this study. The hLMJ-SSP was connected to the miniature mass spectrometer with a 50 cm long flexible tube and controlled by an integrated microcontroller unit (MCU). By simply pressing a button on the probe, automated surface analysis could be carried out and completed within ∼2 min, in which solvent delivery, sample extraction, extract aspiration, injection and MS analysis were performed in sequence. A limit of detection (LOD) as low as 5 pg was achieved. The capability of in-situ surface analysis was also demonstrated by directly analyzing illicit drug residues on fingers and medicines in biological fluids. With the merits of automated operation, high sensitivity and nondestructive analysis, this LMJ-SSP-mini MS system would be a promising tool for various in-situ analytical applications.

Development of a miniature protein mass spectrometer capable of analyzing native proteins.

Current miniature mass spectrometers were usually designed for the detection of small and medium size molecules, including volatile (semi-volatile) compounds, drugs and lipids. In this study, a miniature protein mass spectrometer was developed in this work, which could serve as a biosensor for the rapid identification of proteins as well as their conformations. A linear ion trap with a field radius of 2.5 mm was designed to extend mass range of the instrument to over 6500 Th. Mass resolution and sensitivity of the instrument were also optimized for protein ions by increasing the buffer gas pressure and using a high-gain Faraday detector. It is then demonstrated that the mass spectra of native proteins, such as IgG1, could be acquired by coupling the instrument with a soft electrospray ionization source. As a proof-of-concept demonstration, results suggest that the current instrument could be used to identify target proteins and probe/distinguish their conformations in solutions.

A "Brick" Mass Spectrometer with Photoionization for Direct Analysis of Trace Volatile Compounds.

With high portability and favorable performance, miniature mass spectrometers have become one of the most attractive tools for on-site analysis of trace volatile compounds. Based on the "Brick" mass spectrometer (BMS) developed previously, a hand-held BMS integrated with a photoionization source (PI-BMS) was developed in this study for volatile compound analysis. With compact dimensions of 30 cm × 18.5 cm × 27.6 cm (length × width × height), the PI-BMS was equipped with a 10.6 eV UV lamp and capable of generating molecular ions. The capabilities of qualitative and quantitative analyses for different volatile samples were demonstrated and characterized. Under optimized conditions, high detection sensitivity in open air was obtained for the PI-BMS with a limit of detection (LOD) of ∼10 ppbv. As demonstrations of mixture analysis, four different fresh fruits were directly analyzed using PI-BMS, observing characteristic mass spectra for each type of fruit.

Pseudo-Multiple Reaction Monitoring (Pseudo-MRM) Mode on the "Brick" Mass Spectrometer, Using the Grid-SWIFT Waveform.

Besides portability and increasingly improved performances, the ability of screening target analyte from complex compounds is a crucial function of miniature mass spectrometers, especially for in situ analysis. Selected reaction monitoring (SRM) and multiple reaction monitoring (MRM) operation modes are the most widely used mass spectrometry operation methods for target analyte quantitation. As a continuous effort to improve the analytical performances of the "brick" mass spectrometer, built in-house, pseudo-SRM and pseudo-MRM modes were realized on the linear ion trap mass analyzer in the device. A broadband excitation waveform in both time and frequency domains, namely, the Grid-SWIFT waveform, was constructed and compared with the conventional SWIFT waveform. By isolating target ions during the ion introduction period using the Grid-SWIFT waveform, target ions could be efficiently accumulated inside the ion trap without experiencing space charge effects and interferences from nontarget ions in the samples. As a result, not only the detection sensitivity of the target analyte could be increased, but also the quantitation accuracy over a relatively wide concentration range could be improved.

Boosting the Sensitivity and Selectivity of a Miniature Mass Spectrometer Using a Hybrid Ion Funnel.

Besides high portability, high analytical performances are also crucial concerns for a miniature mass spectrometer to meet the demands in in situ analysis. As a continuous effort in improving analytical performances of the miniature mass spectrometer with continuous atmospheric pressure interface, a hybrid ion funnel was developed and coupled into the system in this study. The hybrid ion funnel consisted of a rectangular ion funnel region and a planar quadrupole field region, which were fabricated by the printed circuit board technology. After systematic optimization, a limit of detection of 1 ng/mL was obtained, which was improved by 10 folds relative to that of 10 ng/mL previously reported for the miniature mass spectrometer. Besides improved ion transmission efficiency, this hybrid ion funnel was also capable of filtering ions according to their mobilities, thus improving the system selectivity. This capability was demonstrated by separation and selective transmission of protein ions at different charge states, reserpine in PEG background and isobaric peptide ions. Resolution of this system was also tested by analyzing isotopic peaks of reserpine. The ppb-level detection sensitivity and isotope resolving capability achieved in this work would greatly expand the application range of miniature mass spectrometers.

Electric modeling and characterization of pulsed high-voltage nanoelectrospray ionization sources by a miniature ion trap mass spectrometer.

A better understanding of nanoelectrospray ionization (nano-ESI) would be beneficial in further improving the performances of nano-ESI. In this work, the pulsed high-voltage (HV) nano-ESI has been electrically modeled and then systematically characterized by both voltage-current and mass spectrometry measurements. First, the equivalent resistance of a nano-ESI source changes with respect to both emitter tip diameter and the HV applied. Increased voltage could improve both spray current and ionization efficiency of the pulsed HV nano-ESI. Compared with conventional DC HV method, a pulsed HV has less heating effect on the capillary tip and thus allowing the application of a much higher voltage onto a nano-ESI source. As a result, a pulsed HV nano-ESI could further boost the ionization efficiency of nano-ESI by employing even higher voltages than conventional DC nano-ESI sources.

[Long-term efficacy and safety of electroacupuncture on improving MMSE in patients with Alzheimer's disease].

OBJECTIVE: To observe the efficacy and safety of electroacupuncture (EA) on improving mini-mental state examination (MMSE) in patients with Alzheimer's disease (AD), and to evaluate the efficacy during follow-up visit. METHODS: Forty patients were randomly divided into a treatment group and a control group, 20 patients in each one (3 patients dropped off in the treatment group and 4 patients in the control group). The patients in the treatment group were treated with acupuncture at Baihui (GV 20), Fengfu (GV 16), Shenting (GV 24), Taiyang (EX-HN 5), Shangyintang (Extra 3) and Dazhong (KI 14); besides, EA was applied at Taiyang (EX-HN 5), Baihui (GV 20) and Shenting (GV 24) with dilatational wave, 10 Hz/50 Hz in frequency, 0.5 to 5.0 mA in intensity, once every two days, three treatments per week. The patients in the control group were treated with oral administration of donepezil hydrochloride tablets, once a day, taken before sleep. The treatment was given for 12 weeks in the two groups. The MMSE was evaluated before treatment, 12 weeks±3 days into treatment, and 24 weeks±7 days after treatment, respectively. RESULTS: The difference of total score of MMSE before and 12 weeks±3 days into treatment was not significant between the two groups (P>0.05); the total score of MMSE after treatment was higher than that before treatment (both P<0.05); compared before treatment, the short-term memory score was increased in the treatment group (P<0.05), and the increasing range was superior to that in the control group (P<0.05). Compared before treatment, the total score of MMSE in the two groups were reduced 24 weeks ±7 days after treatment (both P<0.05), and the reduction in the treatment group was less than that in the control group (P<0.05); the differences of short-term memory score before and after treatment was significant between the two groups (P<0.05). No adverse reaction occurred in the two groups. CONCLUSION: The effect of EA on improving MMSE in patients with AD is similar to donepezil supported by evidence-based medicine. The effect of EA may have a certain continuous effect, and may have advantages in instantaneous memory. In addition, the EA is safe.

Direct bacteria analysis using laserspray ionization miniature mass spectrometry.

An atmospheric pressure laserspray ionization mass spectrometry (AP-LSI mini MS) has been developed and employed in the fast analysis of bacteria. Without using surfactants or any extracting methods, 21 foodborne bacteria from 12 genera were directly analyzed. Typical fingerprints of small molecules and lipids were detected and recognized in the mass spectra with high reproducibility. Furthermore, a supervised multivariate statistics method, orthogonal partial least squares (OPLS), was applied, and these bacteria could be differentiated at both genus and species levels. With improved performance in the future, AP-LSI mini MS could be a simple, effective, and fast approach for direct bacteria analysis on the field.

Direct Biological Sample Analyses by Laserspray Ionization Miniature Mass Spectrometry.

With improved performances, miniature mass spectrometers are becoming suitable for more practical applications. At the same time, the coupling of an approximate ionization source is essential in terms of minimizing sample preparation and broadening the range of samples that could be analyzed. In this study, an atmospheric pressure laserspray ionization (AP-LSI) source was coupled with our home developed miniature ion trap mass spectrometer. The whole system is compact in size, and biological samples could be directly analyzed with minimum sample preparation. Direct detections of peptides, proteins, drugs in whole blood, and urine could be achieved with high sensitivity. The analyses of tissue sections were demonstrated, and different regions in a tissue section could be differentiated based on their lipid profiles. Results suggest that the coupling of AP-LSI with miniature mass spectrometer is a powerful technique, which could potentially benefit target molecule analysis in biological and medical applications.

A "Brick Mass Spectrometer" Driven by a Sinusoidal Frequency Scanning Technique.

In this work, a "brick" size miniature mass spectrometer (28 cm × 21 cm × 16 cm) was developed and characterized, which was enabled by the development of a new frequency scanning technique. Different from the conventional voltage scanning method or the digital waveforms used on a digital ion trap, a sinusoidal frequency scanning technique was developed to drive the linear ion trap of the brick mass spectrometer (BMS). Both an in-vacuum plasma ionization source and an electrospray ionization source were coupled with this BMS for the analyses of volatile and nonvolatile samples. Stability diagram, sensitivity, mass resolution, and mass range of the BMS were explored. This new frequency scanning technique could not only reduce the size and power consumption of a miniature mass spectrometer but also improve its analytical performances, especially in terms of mass range and resolution. Analogous to the development of cell phones, this BMS would be an important step from "brick" mass spectrometer to "cell" mass spectrometer.

Mini Mass Spectrometer Integrated with a Miniature Ion Funnel.

Previously, a continuous atmospheric pressure interfaced miniature mass spectrometer was developed in our lab. The continuous atmospheric pressure interface improves system robustness, stability, and scan speed, but it also results in limited ion transfer efficiency and reduced mass resolution. To solve these problems, a miniature ion funnel was designed and integrated into the miniature mass spectrometer for the first time. Besides ion transfer efficiency, dimension and power consumption of the ion funnel also need to be considered throughout the design process. After a systematic optimization, the designed miniature ion funnel could increase ion transfer efficiency by more than 10 times, while lowering the background pressure of ion trap by ∼2 times. As a result, sensitivity and mass resolution of the second generation miniature mass spectrometer were improved by 20 times and ∼2 times, respectively, while maintaining its high scan speed and stability. A sensitive and robust mini-MS, capable of coupling with ambient ionization sources would meet the needs of many on-site chemical analysis applications, such as in food, drug, and agricultural administrations, forensic science, homeland security, and etc.

Correction: Ion collision cross section analyses in quadrupole ion traps using the filter diagonalization method: a theoretical study.

Correction for 'Ion collision cross section analyses in quadrupole ion traps using the filter diagonalization method: a theoretical study' by Ting Jiang et al., Phys. Chem. Chem. Phys., 2016, 18, 12058-12064.

An aerodynamic assisted miniature mass spectrometer for enhanced volatile sample analysis.

Previously, we have reported the development of a miniature mass spectrometer with a continuous atmospheric pressure interface (CAPI), and the use of it for non-volatile sample analysis, such as drugs, peptides and proteins. However due to the diffusion effects in the CAPI, especially stronger for light ions, the instrument shows low detection sensitivities for volatile samples when coupling with an atmosphere pressure chemical ionization (APCI) source (>ppmv). In this study, an in-vacuum plasma ionization source was designed and integrated into the system. By performing ionization in the first vacuum stage, ion transfer loss through the CAPI was minimized and tens of ppbv level detection sensitivities were achieved for volatile samples. Due to its improved sensitivity, chemical source tracing was demonstrated in an indoor environment as a simple proof-of-concept example. Furthermore, an aerodynamic sampling method was developed to facilitate directional sample transfer towards the miniature mass spectrometer in an open environment. By coupling this aerodynamic method with the miniature mass spectrometer, remote chemical source sensing could be achieved at a distance of more than two meters. This aerodynamic sampling method could also be applied to other mass spectrometry instruments for enhanced sample sampling in open environments.

Acupuncture for Chronic Urinary Retention due to Spinal Cord Injury: A Systematic Review.

No systematic review has been published on the use of acupuncture for the treatment of chronic urinary retention (CUR) due to spinal cord injury (SCI). The aim of this review was to assess the effectiveness and safety of acupuncture for CUR due to SCI. Three randomized controlled trials (RCTs) including 334 patients with CUR due to SCI were included. Meta-analysis showed that acupuncture plus rehabilitation training was much better than rehabilitation training alone in decreasing postvoid residual (PVR) urine volume (MD -109.44, 95% CI -156.53 to -62.35). Likewise, a combination of acupuncture and aseptic intermittent catheterization was better than aseptic intermittent catheterization alone in improving response rates (RR 1.23, 95% CI 1.10 to 1.38). No severe adverse events were reported. In conclusion, acupuncture as a complementary therapy may have a potential effect in CUR due to SCI in decreasing PVR and improving bladder voiding. Additionally, acupuncture may be safe in treating CUR caused by SCI. However, due to the lack of high quality RCTs, we could not draw any definitive conclusions. More well-designed RCTs are needed to provide strong evidence.