minus plus magnify speech newspaper atomic biology chemistry computer-science earth-science forensic-services globe info math matrix molecule neuroscience pencil physics pin psychology email share atsign clock double-left-chevron double-right-chevron envelope fax phone tumblr googleplus pinterest twitter facebook feed linkedin youtube flickr instagram
Nicholas Manicke, Ph.D.



  • Ph.D., Purdue University, 2009


My research focuses on developing new ways of applying mass spectrometry to difficult problems. Mass spectrometry is useful in such diverse fields as biomedical research and clinical testing, forensic science, homeland security, and food safety because of its sensitivity, specificity, and generality. It is difficult to use, however, and typically requires extensive sample preparation prior to analysis. A number of so-called "ambient ionization" methods have been developed. These methods, which include DESI (desorption electrospray ionization) for the chemical analysis of surfaces and Paper Spray for rapid analysis of biological samples, allow for the direct analysis of complex samples without the laborious sample preparation process normally associated with mass spectrometry. The projects in my lab involve both early phase investigation into novel methods, and later phase R&D projects that seek to partner with industrial and government laboratories to translate research into impact.

Analysis of Biofluids by Paper Spray Mass Spectrometry

Paper spray is a new mass spectrometry ionization method that allows for quantitative and qualitative analysis from complex samples without prior sample purification or chromatography. A small volume of biofluid such as blood or urine is deposited on paper, and a small volume of solvent is applied to the paper so that it flows through the sample by capillary action. As the solvent flows through the sample, the chemicals of interest are extracted into the solvent. After the solvent reaches the end of the paper, a high voltage is applied to the moist paper, and an electrospray is induced at the sharp tip of the paper. As the solvent evaporates, gas phase ions of the analyte molecules are generated and detected by a mass spectrometer. The entire analysis requires about 30 seconds and aside from an unmodified mass spectrometer requires nothing more than the paper substrate on which the sample is already stored, microliter amounts of solvent, and an electrical connection to the high voltage connection on the front of the mass spectrometer. Prototype instrumentation has been developed to automate this process (figure 1). Some applications of paper spray mass spectrometry developed by my group are described below.


Figure 1: Novel chemical instrumentation was developed to automate PaperSpray analysis on commercial mass spectrometers. A disposable cartridge with a blood sample being applied is shown in the lower right. This instrument is being commercialized by a company in Indianapolis.


Illicit Drug Monitoring

There is a need to develop simple and fast methods to screen urine samples for pharmaceuticals, illicit drugs, and drug metabolites to assess patient compliance in methadone clinics and pain clinics. Analysis of dried urine spots by PaperSpray-MS is an intriguing technology for this application because 1) it requires no sample preparation 2) the entire urine analysis time is around 1 minute and 3) the use of dried urine spots could simplify sample transportation to the laboratory. Cartridges could be spotting with urine at the clinic and then mailed to the laboratory rather than shipping liquid urine. A typical mass spectrum from a urine sample collected at a methadone clinic is shown in Figure 2. Chemicals naturally present in the urine, including creatinine at m/z 114, were detected. Several peaks consistent with various drug and drug metabolites were found as well including methadone and the primary methadone metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).

Figure 2: Mass spectrum obtained by analyzing urine from a methadone clinic directly by paper spray mass spectrometry


Therapeutic drug monitoring (TDM)

For many therapeutic drugs, measurement of the drug levels in the blood post-dose is known to be of significant value for improving patient outcomes and well-being. Therapeutic drug monitoring is rarely done, however, often because there are not methods available to measure the drug with adequate performance that can also be implemented in a clinical setting. We aim to simplify the process required for analysing drug levels in blood to make TDM more practical.


Tacrolimus is an immunosuppressive drug administered to patients who have received an organ transplant. Monitoring of tacrolimus levels in the blood are known to improve outcomes. PaperSpray MS was used to measure tacrolimus levels in patients and compared to a reference HPLC MS assay. The two methods gave comparable results (figure 3), but PaperSpray is simpler and faster.


Forensic Toxicology

In addition to rapid screening of drugs in urine, paper spray can also be used to quantitatively analyze illicit drug levels in blood. Methods are currently being developed to simultaneously measure panels of commonly abused drugs. Sample data for quantitative analysis of cocaine in blood is shown in figure 4.

Figure 4: Quantitative analysis of cocaine directly from blood using paper spray mass spectrometry


Chemical Imaging of Surfaces DESI Mass Spectrometry

Mass spectrometry imaging is a method for the chemical analysis of surfaces in which the distribution of multiple analytes on a surface can be determined within a single experiment. The approach is typically done by scanning some type of ion-generating probe over a surface and collecting mass spectral data as the probe interrogates the surface. Provided the probe has a well-defined sampling area, the distribution of the chemicals detected by the mass spectrometer can be determined.

Figure 5: Imaging of chemicals within a latent fingerprint by DESI-MS. Detection of cocaine in a LFP on paper (left) and D9-THC in a LFP on glass (right). The intensity of the color indicates the relative intensity of the MS signal.

I am interested in the use of Desorption Electrospray Ionization (DESI), one method for performing mass spectrometry imaging. The distinguishing feature of this method is that sample analysis can be performed on untreated samples in the open air without any sample preparation. A number of compelling applications of this technology have been explored including differentiating between tumor and nontumor tissue and mapping the distribution of drug and drug metabolites within tissue samples for pharmaceutical research. My focus is primarily on the application of this technology to problems in the forensic sciences. One area of research is the imaging of latent fingerprints. DESI is capable of 1) mapping the latent fingerprints with sufficient spatial resolution to recognize the print and 2) identifying the chemical signatures present within the print, such as illicit drugs or explosives that the individual may have touched prior to leaving behind the latent print (figure 5). This information is valuable forensically because the spatial information (i.e. the fingerprint itself) and the chemical information (i.e. the presence of drugs, explosive residues, etc.) are linked together, providing strong evidence that the individual who left the fingerprint handled the material in question.

Publications & Professional Activities

BJ Bills, J Kinkade, G Ren, NE Manicke.  The impacts of paper properties on matrix effects during paper spray mass spectrometry analysis of prescription drugs, fentanyl and synthetic canabinoids.  Forensic Chemistry, 11: 15-22 (2018)

CG Owings, C Skaggs, W Sheriff, N Manicke, CJ Picard.  Chemical Assay for the Detection of Vertebrate Fecal Metabolites in Adult Blow Flies (Diptera: Calliphoridae).  Environmental Entomology, 47(3): 586-593 (2018)

McKenna J, Shanks K, and Manicke NE*: Toxicological Drug Screening using Paper Spray High-Resolution Tandem Mass Spectrometry (HR-MS/MS). Journal of Analytical Toxicology. 42(5): 300-310 (2018) . https://doi.org/10.1093/jat/bky001

Zhang C, Glaros T, and Manicke NE*: Targeted Protein Detection using an All-In-One Mass Spectrometry Cartridge. Journal of the American Chemical Society. 139 (2), 10996-10999 (2017). http://dx.doi.org/10.1021/jacs.7b05571

Fedick PW, Bills BJ, Manicke NE, and Cooks RG: Forensic Sampling and Analysis from a Single Substrate: Surface-Enhanced Raman Spectroscopy Followed by Paper Spray Mass Spectrometry. Analytical Chemistry. 89 (20), 10973-10979 (2017). http://dx.doi.org/10.1021/acs.analchem.7b02798 

Dhummakupt ES, Mach PM, Carmany D, Demond PS, Moran TS, Connell T, Wylie HS, Manicke NE, Nilles JM, and Glaros T: Direct Analysis of Aerosolized Chemical Warfare Simulants Captured on a Modified Glass-Based Substrate by "Paper-Spray" Ionization. Analytical Chemistry. 89 (20), 10866-10872 (2017). http://dx.doi.org/10.1021/acs.analchem.7b02530 

Jett R, Skaggs C, and Manicke NE*: Drug Screening Method Development for Paper Spray Coupled to a Triple Quadrupole Mass Spectrometer. Analytical Methods. 9, 5037-5043 (2017). http://dx.doi.org/10.1039/C7AY01009E

McKenna J, Dhummakupt ES, Connell T, Demond PS, Miller DB, Nilles JM, Manicke NE* and Glaros T*: Detection of Chemical Warfare Agent Simulants and Hydrolysis Products in Biological Samples by Paper Spray Mass Spectrometry. Analyst. 142, 1442-1451 (2017). http://dx.doi.org/10.1039/C7AN00144D

Bills BJ and Manicke NE*: Development of a Prototype Blood Fractionation Cartridge for Plasma Analysis by Paper Spray Mass Spectrometry. Clinical Mass Spectrometry 2, 18-24 (2016). http://dx.doi.org/10.1016/j.clinms.2016.12.002

Vega C+, Spence C+, Zhang C, Bills BJ, Manicke NE*: Ionization Suppression and Recovery in Direct Biofluid Analysis Using Paper Spray Mass Spectrometry. Journal of the American Society of Mass Spectrometry 27(4), 726-734 (2016). http://dx.doi.org/10.1007/s13361-015-1322-8

Shi R-Z, El Gierari ETM, Faix JD, Manicke NE*: Rapid Measurement of Cyclosporine and Sirolimus in Whole Blood by Paper Spray-Tandem Mass Spectrometry. Clinical Chemistry 62 (1), 295-297 (2016). http://dx.doi.org/10.1373/clinchem.2015.245191

Zhang C and Manicke NE*: Development of a Paper Spray Mass Spectrometry Cartridge with Integrated Solid Phase Extraction for Bioanalysis. Analytical Chemistry 87(12), 6212-6219 (2015). http://dx.doi.org/10.1021/acs.analchem.5b00884

Manicke NE* and Belford M: Separation of Opiate Isomers Using Electrospray Ionization and Paper Spray Coupled to High-Field Asymmetric Waveform Ion Mobility Spectrometry. Journal of the American Society for Mass Spectrometry 26(5), 701-705 (2015).http://dx.doi.org/10.1007/s13361-015-1096-z

Shi R-Z, El Gierari ETM, Manicke NE*, Faix JD: Rapid Measurement of Tacrolimus in Whole Blood by Paper Spray-Tandem Mass Spectrometry (PS-MS/MS). Clinica Chimica Acta 441, 99-104 (2015). http://dx.doi.org/10.1016/j.cca.2014.12.022

Espy RD, Teunissen SF, Manicke NE, Ren Y, Ouyang Z, Van Asten A, Cooks RG: Paper Spray and Extraction Spray Mass Spectrometry for the Direct and Simultaneous Quantification of Eight Drugs of Abuse in Whole Blood. Analytical Chemistry 86(15), 7712-7718 (2014). http://dx.doi.org/10.1021/ac5016408

Wang H, Ren Y, Mcluckey MN, Manicke NE, Park J, Zheng LX, Shi RY, Cooks RG, Ouyang Z: Direct Quantitative Analysis of Nicotine Alkaloids from Biofluid Samples Using Paper Spray Mass Spectrometry. Analytical Chemistry 85(23), 11540-11544 (2013). http://dx.doi.org/10.1021/ac402798mManicke NE, Abu-Rabie P, Spooner N, Ouyang Z, Cooks RG: Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring. Journal of the American Society for Mass Spectrometry 22(9), 1501-1507 (2011). http://dx.doi.org/10.1007/s13361-011-0177-x

Cooks RG, Manicke NE, Dill AL, Ifa DR, Eberlin LS, Costa AB, Wang H, Huang GM, Zheng OY: New Ionization Methods and Miniature Mass Spectrometers for Biomedicine: Desi Imaging for Cancer Diagnostics and Paper Spray Ionization for Therapeutic Drug Monitoring.Faraday Discussions 149, 247-267 (2011). http://dx.doi.org/10.1039/c005327a

Manicke NE, Dill AL, Ifa DR, Cooks RG: High-Resolution Tissue Imaging on an Orbitrap Mass Spectrometer by Desorption Electrospray Ionization Mass Spectrometry. Journal of Mass Spectrometry 45(2), 223-226 (2010). http://dx.doi.org/10.1002/jms.1707

Ifa DR, Manicke NE, Dill AL, Cooks G: Latent Fingerprint Chemical Imaging by Mass Spectrometry. Science 321(5890), 805-805 (2008). http://dx.doi.org/10.1126/science.1157199

Give Now