Colorectal Cancer Diagnosis through Breath Test Using a Portable Breath Analyzer-Preliminary Data.

Screening methods available for colorectal cancer (CRC) to date are burdened by poor reliability and low patient adherence and compliance. An altered pattern of volatile organic compounds (VOCs) in exhaled breath has been proposed as a non-invasive potential diagnostic tool for distinguishing CRC patients from healthy controls (HC). The aim of this study was to evaluate the reliability of an innovative portable device containing a micro-gas chromatograph in enabling rapid, on-site CRC diagnosis through analysis of patients' exhaled breath. In this prospective trial, breath samples were collected in a tertiary referral center of colorectal surgery, and analysis of the chromatograms was performed by the Biomedical Engineering Department. The breath of patients with CRC and HC was collected into Tedlar bags through a Nafion filter and mouthpiece with a one-way valve. The breath samples were analyzed by an automated portable gas chromatography device. Relevant volatile biomarkers and discriminant chromatographic peaks were identified through machine learning, linear discriminant analysis and principal component analysis. A total of 68 subjects, 36 patients affected by histologically proven CRC with no evidence of metastases and 32 HC with negative colonoscopies, were enrolled. After testing a training set (18 CRC and 18 HC) and a testing set (18 CRC and 14 HC), an overall specificity of 87.5%, sensitivity of 94.4% and accuracy of 91.2% in identifying CRC patients was found based on three VOCs. Breath biopsy may represent a promising non-invasive method of discriminating CRC patients from HC.

1D-Guided Differential Rescaling of a Contour Plot in Comprehensive 2D Gas Chromatography.

A 1D-guided differential rescaling algorithm for a contour plot is developed based on our recently proposed comprehensive two-dimensional gas chromatography (GC × GC) system with a first-dimensional (1D) detector added. Chromatograms obtained from 1D and second-dimensional (2D) detectors are both incorporated during the data processing. As compared to the conventional contour plot methods using only 2D data, our algorithm can significantly improve precision and consistency of GC × GC results in terms of retention times, peak widths, and peak areas or volumes, regardless of modulation time selection, modulation phase shift fluctuations, and modulation duty cycle. The peak identification, quantification, and capacity can therefore be enhanced. Furthermore, the 1D-guided differential rescaling method is shown to better handle the coelution and missing peak issues often encountered in the conventional methods. Finally, the new method exhibits high versatility in 1D and 2D detector selection, which greatly broadens GC × GC utility. Our method can easily be adapted to other two-dimensional chromatography systems that have direct access to 1D chromatograms.

Automated Gas Chromatography Peak Alignment: A Deep Learning Approach using Greedy Optimization and Simulation.

The clinical significance of volatile organic compounds (VOC) in detecting diseases has been established over the past decades. Gas chromatography (GC) devices enable the measurement of these VOCs. Chromatographic peak alignment is one of the important yet challenging steps in analyzing chromatogram signals. Traditional semi-automated alignment algorithms require manual intervention by an operator which is slow, expensive and inconsistent. A pipeline is proposed to train a deep-learning model from artificial chromatograms simulated from a small, annotated dataset, and a postprocessing step based on greedy optimization to align the signals.Clinical Relevance- Breath VOCs have been shown to have a significant diagnostic power for various diseases including asthma, acute respiratory distress syndrome and COVID-19. Automatic analysis of chromatograms can lead to improvements in the diagnosis and management of such diseases.

Retention Time Trajectory Matching for Peak Identification in Chromatographic Analysis.

Retention time drift caused by fluctuations in physical factors such as temperature ramping rate and carrier gas flow rate is ubiquitous in chromatographic measurements. Proper peak matching and identification across different chromatograms is critical prior to any subsequent analysis but is challenging without using mass spectrometry. The purpose of this work was to describe and validate a peak matching and identification method called retention time trajectory (RTT) matching that can be used in targeted analyses free of mass spectrometry. This method uses chromatographic retention times as the only input and identifies peaks associated with any subset of a predefined set of target compounds. An RTT is a two-dimensional (2D) curve formed uniquely by the retention times of the chromatographic peaks. The RTTs obtained from the chromatogram of a sample under test and those pre-installed in a library are matched and statistically compared. The best matched pair implies identification. Unlike most existing peak-alignment methods, no mathematical warping or transformation is involved. Based on the experimentally characterized RTT, an RTT hybridization method was also developed to rapidly generate more RTTs and expand the library without performing actual time-consuming chromatographic measurements, which enables successful peak matching even for chromatograms with severe retention time drifts. Additionally, 3.15 × 105 tests using experimentally obtained gas chromatograms and 2 × 1012 tests using two publicly available fruit metabolomics datasets validated the proposed method, demonstrating real-time peak/interferent identification.

Portable Breath-Based Volatile Organic Compound Monitoring for the Detection of COVID-19 During the Circulation of the SARS-CoV-2 Delta Variant and the Transition to the SARS-CoV-2 Omicron Variant.

Importance: Breath analysis has been explored as a noninvasive means to detect COVID-19. However, the impact of emerging variants of SARS-CoV-2, such as Omicron, on the exhaled breath profile and diagnostic accuracy of breath analysis is unknown. Objective: To evaluate the diagnostic accuracies of breath analysis on detecting patients with COVID-19 when the SARS-CoV-2 Delta and Omicron variants were most prevalent. Design, Setting, and Participants: This diagnostic study included a cohort of patients who had positive and negative test results for COVID-19 using reverse transcriptase polymerase chain reaction between April 2021 and May 2022, which covers the period when the Delta variant was overtaken by Omicron as the major variant. Patients were enrolled through intensive care units and the emergency department at the University of Michigan Health System. Patient breath was analyzed with portable gas chromatography. Main Outcomes and Measures: Different sets of VOC biomarkers were identified that distinguished between COVID-19 (SARS-CoV-2 Delta and Omicron variants) and non-COVID-19 illness. Results: Overall, 205 breath samples from 167 adult patients were analyzed. A total of 77 patients (mean [SD] age, 58.5 [16.1] years; 41 [53.2%] male patients; 13 [16.9%] Black and 59 [76.6%] White patients) had COVID-19, and 91 patients (mean [SD] age, 54.3 [17.1] years; 43 [47.3%] male patients; 11 [12.1%] Black and 76 [83.5%] White patients) had non-COVID-19 illness. Several patients were analyzed over multiple days. Among 94 positive samples, 41 samples were from patients in 2021 infected with the Delta or other variants, and 53 samples were from patients in 2022 infected with the Omicron variant, based on the State of Michigan and US Centers for Disease Control and Prevention surveillance data. Four VOC biomarkers were found to distinguish between COVID-19 (Delta and other 2021 variants) and non-COVID-19 illness with an accuracy of 94.7%. However, accuracy dropped substantially to 82.1% when these biomarkers were applied to the Omicron variant. Four new VOC biomarkers were found to distinguish the Omicron variant and non-COVID-19 illness (accuracy, 90.9%). Breath analysis distinguished Omicron from the earlier variants with an accuracy of 91.5% and COVID-19 (all SARS-CoV-2 variants) vs non-COVID-19 illness with 90.2% accuracy. Conclusions and Relevance: The findings of this diagnostic study suggest that breath analysis has promise for COVID-19 detection. However, similar to rapid antigen testing, the emergence of new variants poses diagnostic challenges. The results of this study warrant additional evaluation on how to overcome these challenges to use breath analysis to improve the diagnosis and care of patients.

Portable comprehensive two-dimensional micro-gas chromatography using an integrated flow-restricted pneumatic modulator.

Two-dimensional (2D) gas chromatography (GC) provides enhanced vapor separation capabilities in contrast to conventional one-dimensional GC and is useful for the analysis of highly complex chemical samples. We developed a microfabricated flow-restricted pneumatic modulator (FRPM) for portable comprehensive 2D micro-GC (µGC), which enables rapid 2D injection and separation without compromising the 1D separation speed and eluent peak profiles. 2D injection characteristics such as injection peak width and peak height were fully characterized by using flow-through micro-photoionization detectors (µPIDs) at the FRPM inlet and outlet. A 2D injection peak width of ~25 ms could be achieved with a 2D/1D flow rate ratio over 10. The FRPM was further integrated with a 0.5-m long 2D µcolumn on the same chip, and its performance was characterized. Finally, we developed an automated portable comprehensive 2D µGC consisting of a 10 m OV-1 1D µcolumn, an integrated FRPM with a built-in 0.5 m polyethylene glycol 2D µcolumn, and two µPIDs. Rapid separation of 40 volatile organic compounds in ~5 min was demonstrated. A hybrid 2D contour plot was constructed by using both 1D and 2D chromatograms obtained with the two µPIDs at the end of the 1D and 2D µcolumns, which was enabled by the presence of the flow resistor in the FRPM.

Strongly enhanced THz generation enabled by a graphene hot-carrier fast lane.

Semiconductor photoconductive switches are useful and versatile emitters of terahertz (THz) radiation with a broad range of applications in THz imaging and time-domain spectroscopy. One fundamental challenge for achieving efficient ultrafast switching, however, is the relatively long carrier lifetime in most common semiconductors. To obtain picosecond ultrafast pulses, especially when coupled with waveguides/transmission lines, semiconductors are typically engineered with high defect density to reduce the carrier lifetimes, which in turn lowers the overall power output of the photoconductive switches. To overcome this fundamental trade-off, here we present a new hybrid photoconductive switch design by engineering a hot-carrier fast lane using graphene on silicon. While photoexcited carriers are generated in the silicon layer, similar to a conventional switch, the hot carriers are transferred to the graphene layer for efficient collection at the contacts. As a result, the graphene-silicon hybrid photoconductive switch emits THz fields with up to 80 times amplitude enhancement compared to its graphene-free counterpart. These results both further the understanding of ultrafast hot carrier transport in such hybrid systems and lay the groundwork toward intrinsically more powerful THz devices based on 2D-3D hybrid heterostructures.

A Microcolumn DC Graphene Sensor for Rapid, Sensitive, and Universal Chemical Vapor Detection.

Nearly all existing direct current (DC) chemical vapor sensing methodologies are based on charge transfer between sensor and adsorbed molecules. However, the high binding energy at the charge-trapped sites, which is critical for high sensitivity, significantly slows sensors' responses and makes the detection of nonpolar molecules difficult. Herein, by exploiting the incomplete screening effect of graphene, we demonstrate a DC graphene electronic sensor for rapid (subsecond) and sensitive (ppb) detection of a broad range of vapor analytes, including polar, nonpolar, organic, and inorganic molecules. Molecular adsorption induced capacitance change in the graphene transistor is revealed to be the main sensing mechanism. A novel sensor design, which integrates a centimeter-scale graphene transistor and a microfabricated flow column, is pioneered to enhance the fringing capacitive gating effect. Our work provides an avenue for a broad spectrum real-time gas sensing technology and serves as an ideal testbed for probing molecular physisorption on graphene.

Real Time Breath Analysis Using Portable Gas Chromatography for Adult Asthma Phenotypes.

Asthma is heterogeneous but accessible biomarkers to distinguish relevant phenotypes remain lacking, particularly in non-Type 2 (T2)-high asthma. Moreover, common clinical characteristics in both T2-high and T2-low asthma (e.g., atopy, obesity, inhaled steroid use) may confound interpretation of putative biomarkers and of underlying biology. This study aimed to identify volatile organic compounds (VOCs) in exhaled breath that distinguish not only asthmatic and non-asthmatic subjects, but also atopic non-asthmatic controls and also by variables that reflect clinical differences among asthmatic adults. A total of 73 participants (30 asthma, eight atopic non-asthma, and 35 non-asthma/non-atopic subjects) were recruited for this pilot study. A total of 79 breath samples were analyzed in real-time using an automated portable gas chromatography (GC) device developed in-house. GC-mass spectrometry was also used to identify the VOCs in breath. Machine learning, linear discriminant analysis, and principal component analysis were used to identify the biomarkers. Our results show that the portable GC was able to complete breath analysis in 30 min. A set of nine biomarkers distinguished asthma and non-asthma/non-atopic subjects, while sets of two and of four biomarkers, respectively, further distinguished asthmatic from atopic controls, and between atopic and non-atopic controls. Additional unique biomarkers were identified that discriminate subjects by blood eosinophil levels, obese status, inhaled corticosteroid treatment, and also acute upper respiratory illnesses within asthmatic groups. Our work demonstrates that breath VOC profiling can be a clinically accessible tool for asthma diagnosis and phenotyping. A portable GC system is a viable option for rapid assessment in asthma.

p-Phosphonic acid calix[8]arene mediated synthesis of ultra-large, ultra-thin, single-crystal gold nanoplatelets.

Single-crystal Au nanoplatelets, as large as 28 µm in cross section and as thin as 6 nm, are generated by bubbling hydrogen gas into an aqueous solution of HAuCl4 in the presence of p-phosphonic acid calix[8]arene, which acts as both a catalyst and stabiliser. The use of the ultrathin Au nanoplatelets in oxygen gas sensing has also been established.

Nanoelectronic Heterodyne Sensor: A New Electronic Sensing Paradigm.

Nanoelectronic devices based on nanomaterials such as nanowires, carbon nanotubes, graphene, and other 2D nanomaterials offer extremely large surface-to-volume ratios, high carrier mobility, low power consumption, and high compatibility for integration with modern electronic technologies. These distinct advantages promise great potential for nanoelectronic devices as next generation chemical and biological sensors. Currently, majority of existing nanoelectronic sensors are direct current (DC) sensors, which rely ubiquitously on detection of conductance change associated with molecular adsorption. However, despite the simplicity of the conventional DC sensing technology, it also has severe limitations such as the Debye screening effect in ionic solutions, and the speed-sensitivity trade-off for the detection of charge-neutral molecules. Hence, the development of nanoelectronic sensors calls for new sensing platform technologies that can truly showcase the advantages of electronic sensors. In this Account, we will summarize recent efforts from our group on the development of a new electronic sensing paradigm, the nanoelectronic heterodyne sensors. Unlike conventional charge-detection based sensors, the heterodyne sensor explores the frequency mixing response between molecular dipoles and a nanoscale transistor. As an example, we first discuss the capability of heterodyne sensing in gas sensing applications by using graphene devices. Rapid (down to 0.1 s) and sensitive (down to 1 ppb) detection of a wide range of vapor analytes is achieved, representing orders of magnitude improvement over state-of-the-art nanoelectronic sensors. Furthermore, the heterodyne sensing technique enables electrical probing and tuning of the noncovalent physisorption of polar molecules on graphene surface for the first time. These results provide insight into small molecule-nanomaterial interaction dynamics and signify the ability to electrically tailor interactions, which can lead to rational designs of complex chemical processes for catalysis and drug discovery. Finally, we discuss the application of heterodyne sensing in solution for chemical and biological sensors by using carbon nanotube devices. The fundamental ionic screening effect can be mitigated by operating carbon nanotube field effect transistor as a heterodyne biosensor. Electrical detection of streptavidin binding to biotin in 100 mM buffer solution can be achieved at a frequency beyond 1 MHz. The results should promise a new biosensing platform for point-of-care detection, where biosensors functioning directly in physiologically relevant condition are desired.

Electrical Probing and Tuning of Molecular Physisorption on Graphene.

The ability to tune the molecular interaction electronically can have profound impact on wide-ranging scientific frontiers in catalysis, chemical and biological sensor development, and the understanding of key biological processes. Despite that electrochemistry is routinely used to probe redox reactions involving loss or gain of electrons, electrical probing and tuning of the weaker noncovalent interactions, such as molecular physisorption, have been challenging, primarily due to the inability to change the work function of conventional metal electrodes. To this end, we report electrical probing and tuning of the noncovalent physisorption of polar molecules on graphene surface by using graphene nanoelectronic heterodyne sensors. Temperature-dependent molecular desorptions for six different polar molecules were measured in real-time to study the desorption kinetics and extract the binding affinities. More importantly, we demonstrate electrical tuning of molecule-graphene binding kinetics through electrostatic gating of graphene; the molecular desorption can be slowed down nearly three times within a gate voltage range of 15 V. Our results provide insight into small molecule-nanomaterial interaction dynamics and signify the ability to electrically tailor interactions, which can lead to rational designs of complex chemical processes for catalysis and drug discovery.

Hydrogen induced p-phosphonic acid calix[8]arene controlled growth of Ru, Pt and Pd nanoparticles.

Monodispersed Ru, Pt and Pd nanoparticles with narrow size distributions (2, 12 and 20 nm respectively) have been synthesised via bubbling hydrogen gas into aqueous solutions of the noble metal ions in the presence of p-phosphonic acid calix[8]arene, at room temperature. Molecular modelling of the Ru nanoparticles provides insight into the role of the calixarene in controlling the size and stabilisation of the metal nanoparticles.

Self-assembled calixarene aligned patterning of noble metal nanoparticles on graphene.

Patterns of noble metal nanoparticles (NMNPs) of ruthenium and platinum are formed on p-phosphonic acid calix[8]arene stabilised graphene in water. This involves hydrogen gas induced reduction of metal ions absorbed on the stabilised graphene, with TEM revealing the patterns being comprised of domains of parallel arrays of NMNPs ∼7 nm apart. The domains are orientated in three directions on each graphene sheet at an angle of ∼60° or ∼120° with respect to each other. AFM of self-assembled p-phosphonic acid calix[8]arene on the surface of a highly ordered pyrolytic graphite (HOPG) revealed a similar pattern, implying that the orientation of the assembly of p-phosphonic acid calix[8]arene is governed by the hexagonal motif of graphite/graphene.

Nitrate uptake by p-phosphonic acid calix[8]arene stabilized graphene.

In situ sonic probe exfoliated graphene sheets in the presence of various concentrations of p-phosphonic acid calix[8]arene are effective in removing nitrate from aquatic effluents, with the efficiency increasing for higher ratios of calixarene to graphite. Mild sonication of the nitrate-adsorbed material releases some nitrate ions back to the effluent.

Biomolecule-assisted construction of cadmium sulfide hollow spheres with structure-dependent photocatalytic activity.

In this study, we report the synthesis of monodispersive solid and hollow CdS spheres with structure-dependent photocatalytic abilities for dye photodegradation. The monodispersive CdS nanospheres were constructed with the assistance of the soulcarboxymthyi chitosan biopolymer under hydrothermal conditions. The solid CdS spheres were corroded by ammonia to form hollow CdS nanospheres through a dissolution-reprecipitation mechanism. Their visible-light photocatalytic activities were investigated, and the results show that both the solid and the hollow CdS spheres have visible-light photocatalytic abilities for the photodegradation of dyes. The photocatalytic properties of the CdS spheres were demonstrated to be structure dependent. Although the nanoparticles comprising the hollow spheres have larger sizes than those comprising the solid spheres, the hollow CdS spheres have better photocatalytic performances than the solid CdS spheres, which can be attributed to the special hollow structure.

A versatile approach for decorating 2D nanomaterials with Pd or Pt nanoparticles.

Bubbling H(2) into colloidal suspensions of 2D sheets of graphene or h-BN stabilised in water with p-phosphonic acid calix[8]arene, and pre-treated to bind Pd(II) or Pt(IV) species to their surfaces, is effective in decorating the material with nanoparticles of the noble metals approximately 5 nm in diameter.