MasSpecPen

The MasSpec Pen, or the precìso MasSpec Pen System, is a mass spectrometry (MS) based cancer detection and diagnosis system that can be used for ex vivo[1] and in vivo[2] tissue sample analysis. The system collects biological molecules from a tissue sample surface via a solid-liquid extraction mechanism and transports the molecules to a mass spectrometer for analysis. The composition of the extracted molecules can then be used to predict if the tissue sample analyzed contains cancerous cells using machine learning algorithms and statistical models. In early-stage clinical research, the MasSpec Pen system was able to distinguish various cancer tissues, including thyroid, breast, lung, and ovarian tumor tissues, from their normal counterparts with an overall accuracy of 96.3%.[1] A follow-up study in illustrating the use of the device for detection of serous ovarian carcinoma in ex vivo tissue biopsies allowed for the discrimination of normal and cancerous ovarian samples with a clinical sensitivity and specificity of 94.0% and 94.4%, respectively.[3]

Development and current usage

Livia S. Eberlin, Ph.D., an Assistant Professor of Chemistry at the University of Texas at Austin, first reported the invention of the MasSpec Pen in 2017. Within her laboratory, the device has been used to analyze human tissue biopsies, including normal and cancerous breast, lung, ovarian, and thyroid samples.[1][3] The MasSpec Pen is currently being evaluated for use on freshly excised tissue biopsies and for intraoperative use during oncology surgeries.[4]

The MasSpec Pen has been licensed to Genio Technologies, Inc., a subsidiary of MS Pen Technologies, Inc.[5]

Principle of operation

Ambient ionization mass spectrometry for disease diagnosis

The MasSpec Pen technology is based on the principles of ambient ionization, in which ions are generated directly from a sample without need for extensive sample preparation or chromatographic separations.[6][7] The MasSpec Pen can further be categorized as a solid-liquid extraction based ambient ionization method, described as methods that utilize a solvent system to gently extract molecules from a sample surface that are subsequently analyzed by a mass spectrometer.[8] Desorption electrospray ionization (DESI) was the first liquid-based ambient ionization MS method.[6] DESI employed a spray of charged solvent droplets to bombard a sample surface to desorb and ionize molecules from the sample surface, which are then directed towards and analyzed by a mass spectrometer. DESI-MS and other solvent-based ambient ionization MS methods has been widely employed for the analysis of small molecules, primarily metabolites and lipids, directly from biological tissue specimens to determine their molecular composition and leverage the mass spectral data acquired for diagnostic purposes.[9][10][11][12] These methods have been deployed for the discrimination of normal and cancerous regions of tissue samples for many solid tumor indications, including breast,[13][14] brain,[15][16][17] prostate,[18][19] ovarian,[20][21] and colorectal,[22] among others.[23][24][25] Multivariate statistical analysis methods are often utilized to generate statistical models from the mass spectral data acquired from direct analysis of tissue samples to distinguish between healthy and diseased tissues.

MasSpec Pen analysis mechanism

The MasSpec Pen, initially described in 2017, is a solvent-based ambient ionization technique but differs from its predecessors due to the handheld nature of the device, allowing analysis of samples distant from the mass spectrometer in a geometry independent manner.[1] The MasSpec Pen used a probe that can be manipulated by hand to direct the analysis. To use the system, the tip of the 'pen' is placed in contact with the surface to be sampled and the user triggers the initiation of a sampling procedure by pressing an integrated foot pedal. This signals a syringe pump to deliver a small aliquot of solvent through a polymer tube to a reservoir at the tip of the 'pen' that remains in contact with the sample. Analytes are then extracted from the sample into the solvent droplet by a solid-liquid extraction mechanism. After a 3 second extraction period, the droplet is aspirated into the mass spectrometer using the vacuum from the mass spectrometer as the vacuum source. Once inside the mass spectrometer, the analytes within the solvent droplet are de-solvated and ionized via an inlet ionization mechanism. The ionized molecules are then analyzed by the mass spectrometer analyzer and the mass spectrum resulting is generated.

Cancer diagnosis with the MasSpec Pen

The MasSpec Pen was designed to assist in the detection of positive surgical margins during solid tumor debulking procedures to assist in the complete excision of cancer surgeries. The device was initially used to analyze 253 human tissue biopsies, including normal and cancerous breast, lung, ovary, and thyroid tissues.[1] The mass spectra obtained for each sample contained metabolites, lipids, and some proteins that were representative of the molecular composition of the tissue analyzed. The collected data for each tissue type was then used to develop statistical models that could discriminate between the normal and cancer samples of each tissue type. Leave-one-patient-out cross validation was used to evaluate the accuracy of the models for distinguishing the normal and cancer tissues based on their molecular profiles. The method allowed for diagnosis of the breast tissues with 95.6% accuracy, lung with 96.8% accuracy, and ovary with 94.7% accuracy. Statistical models also allowed for the discrimination of normal thyroid from papillary thyroid carcinomas with 97.8% accuracy and from follicular thyroid adenomas with 94.7% accuracy. The report also demonstrated the ability of the MasSpec Pen technology to detect cancer within regions of mixed tissue containing both normal and cancerous cells from an ovarian cancer sample. Finally, the authors demonstrated the use of this method for in vivo analysis of tumor tissues using an anesthetized murine model.

Performance of the MasSpec Pen for ovarian cancer diagnosis was further evaluated in a report published in 2019.[3] The authors analyzed 160 human ovarian tissue samples, including 78 normal ovary and 82 serous carcinomas, with the MasSpec Pen and developed classification models to discriminate between the normal and cancer samples. The model was able to distinguish between the normal and cancerous ovarian samples with 98.3%, 100.0%, and 92.3% overall accuracy on a training, validation, and test set of samples. Further, the report evaluated the ability of the MasSpec Pen system to distinguish ovarian cancer from fallopian tube and peritoneum tissue, two of the most common sites for ovarian cancer metastasis. Accuracies of 87.9% and 92.6% were achieved for the discrimination of cancer from fallopian tube and peritoneum tissues, respectively.

The MasSpec Pen has also been implemented for the detection of pancreatic cancer during excision procedures.[26] The MasSpec Pen was used on both ex vivo and in vivo tissue samples to discriminate between healthy pancreas and pancreatic tumor tissue. The device was also used to detect cancerous margins near adjacent structures of the pancreas such as the bile duct. The system was used in 18 pancreatic cancer surgeries and the data collected allowed the detection of cancerous tissue with high accuracy.

References

  1. 1 2 3 4 5 Zhang J, Rector J, Lin JQ, Young JH, Sans M, Katta N, et al. (September 2017). "Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system". Science Translational Medicine. 9 (406): eaan3968. doi:10.1126/scitranslmed.aan3968. PMC 5830136. PMID 28878011.
  2. ↑ Keating MF, Zhang J, Feider CL, Retailleau S, Reid R, Antaris A, et al. (September 2020). "Integrating the MasSpec Pen to the da Vinci Surgical System for In Vivo Tissue Analysis during a Robotic Assisted Porcine Surgery". Analytical Chemistry. 92 (17): 11535–11542. doi:10.1021/acs.analchem.0c02037. PMID 32786489. S2CID 221126047.
  3. 1 2 3 Zhang, Jialing; Sans, Marta; DeHoog, Rachel J.; Garza, Kyana Y.; King, Mary E.; Feider, Clara L.; Bensussan, Alena; Keating, Michael F.; Lin, John Q.; Povilaitis, Sydney; Katta, Nitesh; Milner, Thomas E.; Yu, Wendong; Nagi, Chandandeep; Dhingra, Sadhna; Pirko, Christopher; Brahmbhatt, Kirtan A.; Van Buren, George; Carter, Stacey; Fisher, William E.; Thompson, Alastair; Grogan, Raymon H.; Suliburk, James; Eberlin, Livia S. (December 16, 2020). "Direct Molecular Analysis of In Vivo and Freshly Excised Tissues in Human Surgeries with the MasSpec Pen Technology". medRxiv 10.1101/2020.12.14.20248101v1.
  4. ↑ Zhang J, Sans M, DeHoog RJ, Garza KY, King ME, Feider CL, et al. (December 16, 2020). "Direct Molecular Analysis of In Vivo and Freshly Excised Tissues in Human Surgeries with the MasSpec Pen Technology". medRxiv 10.1101/2020.12.14.20248101v1.
  5. ↑ Seagraves S (23 January 2020). "i2E Management Co., Inc. leads $1.25 million investment in Tulsa-based MS Pen Technologies, Inc". i2E.
  6. 1 2 Cooks RG, Ouyang Z, Takats Z, Wiseman JM (March 2006). "Detection Technologies. Ambient mass spectrometry". Science. 311 (5767): 1566–70. doi:10.1126/science.1119426. PMID 16543450. S2CID 98131681.
  7. ↑ Domin M, Cody R, eds. (2014). Ambient Ionization Mass Spectrometry. New Developments in Mass Spectrometry. Cambridge: Royal Society of Chemistry. doi:10.1039/9781782628026. ISBN 978-1-84973-926-9.
  8. ↑ Laskin J, Lanekoff I (January 2016). "Ambient Mass Spectrometry Imaging Using Direct Liquid Extraction Techniques". Analytical Chemistry. 88 (1): 52–73. doi:10.1021/acs.analchem.5b04188. PMC 5767520. PMID 26566087.
  9. ↑ Eberlin LS, Ferreira CR, Dill AL, Ifa DR, Cooks RG (November 2011). "Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1811 (11): 946–60. doi:10.1016/j.bbalip.2011.05.006. PMC 3205348. PMID 21645635.
  10. ↑ Cabral EC, Ifa DR (2015). "DESI Imaging of Small Molecules in Biological Tissues". Mass Spectrometry Imaging of Small Molecules. Methods in Molecular Biology. Vol. 1203. Clifton, N.J. pp. 63–77. doi:10.1007/978-1-4939-1357-2_7. ISBN 978-1-4939-1356-5. PMID 25361667.{{cite book}}: CS1 maint: location missing publisher (link)
  11. ↑ Ifa DR, Eberlin LS (January 2016). "Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation". Clinical Chemistry. 62 (1): 111–23. doi:10.1373/clinchem.2014.237172. PMC 5315420. PMID 26555455.
  12. ↑ Li N, Nie H, Jiang L, Ruan G, Du F, Liu H (August 2020). "Recent advances of ambient ionization mass spectrometry imaging in clinical research". Journal of Separation Science. 43 (15): 3146–3163. doi:10.1002/jssc.202000273. PMID 32573988. S2CID 219986812.
  13. ↑ Porcari AM, Zhang J, Garza KY, Rodrigues-Peres RM, Lin JQ, Young JH, et al. (October 2018). "Multicenter Study Using Desorption-Electrospray-Ionization-Mass-Spectrometry Imaging for Breast-Cancer Diagnosis". Analytical Chemistry. 90 (19): 11324–11332. doi:10.1021/acs.analchem.8b01961. PMC 7433752. PMID 30170496.
  14. ↑ Calligaris D, Caragacianu D, Liu X, Norton I, Thompson CJ, Richardson AL, et al. (October 2014). "Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis". Proceedings of the National Academy of Sciences of the United States of America. 111 (42): 15184–9. Bibcode:2014PNAS..11115184C. doi:10.1073/pnas.1408129111. PMC 4210338. PMID 25246570.
  15. ↑ Eberlin LS, Norton I, Orringer D, Dunn IF, Liu X, Ide JL, et al. (January 2013). "Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors". Proceedings of the National Academy of Sciences of the United States of America. 110 (5): 1611–6. Bibcode:2013PNAS..110.1611E. doi:10.1073/pnas.1215687110. PMC 3562800. PMID 23300285.
  16. ↑ Pirro V, Jarmusch AK, Ferreira CR, Cooks RG (2017). "Ambient Lipidomic Analysis of Brain Tissue Using Desorption Electrospray Ionization (DESI) Mass Spectrometry". In Wood P (ed.). Lipidomics. Neuromethods. Vol. 125. New York, NY: Springer New York. pp. 187–210. doi:10.1007/978-1-4939-6946-3_14. ISBN 978-1-4939-6944-9.
  17. ↑ Agar NY, Golby AJ, Ligon KL, Norton I, Mohan V, Wiseman JM, et al. (February 2011). "Development of stereotactic mass spectrometry for brain tumor surgery". Neurosurgery. 68 (2): 280–89, discussion 290. doi:10.1227/neu.0b013e3181ff9cbb. PMC 3678259. PMID 21135749.
  18. ↑ Kerian KS, Jarmusch AK, Pirro V, Koch MO, Masterson TA, Cheng L, Cooks RG (February 2015). "Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry". The Analyst. 140 (4): 1090–8. Bibcode:2015Ana...140.1090K. doi:10.1039/C4AN02039A. PMC 4314440. PMID 25521825.
  19. ↑ Banerjee S, Zare RN, Tibshirani RJ, Kunder CA, Nolley R, Fan R, et al. (March 2017). "Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids". Proceedings of the National Academy of Sciences of the United States of America. 114 (13): 3334–3339. Bibcode:2017PNAS..114.3334B. doi:10.1073/pnas.1700677114. PMC 5380053. PMID 28292895.
  20. ↑ Sans M, Gharpure K, Tibshirani R, Zhang J, Liang L, Liu J, et al. (June 2017). "Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging". Cancer Research. 77 (11): 2903–2913. doi:10.1158/0008-5472.CAN-16-3044. PMC 5750373. PMID 28416487.
  21. ↑ Dória ML, McKenzie JS, Mroz A, Phelps DL, Speller A, Rosini F, et al. (December 2016). "Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging". Scientific Reports. 6 (1): 39219. Bibcode:2016NatSR...639219D. doi:10.1038/srep39219. PMC 5156945. PMID 27976698.
  22. ↑ Gerbig S, Golf O, Balog J, Denes J, Baranyai Z, Zarand A, et al. (June 2012). "Analysis of colorectal adenocarcinoma tissue by desorption electrospray ionization mass spectrometric imaging". Analytical and Bioanalytical Chemistry. 403 (8): 2315–25. doi:10.1007/s00216-012-5841-x. PMID 22447214. S2CID 25423493.
  23. ↑ DeHoog RJ, Zhang J, Alore E, Lin JQ, Yu W, Woody S, et al. (October 2019). "Preoperative metabolic classification of thyroid nodules using mass spectrometry imaging of fine-needle aspiration biopsies". Proceedings of the National Academy of Sciences of the United States of America. 116 (43): 21401–21408. Bibcode:2019PNAS..11621401D. doi:10.1073/pnas.1911333116. PMC 6815148. PMID 31591199.
  24. ↑ Eberlin LS, Margulis K, Planell-Mendez I, Zare RN, Tibshirani R, Longacre TA, et al. (August 2016). "Pancreatic Cancer Surgical Resection Margins: Molecular Assessment by Mass Spectrometry Imaging". PLOS Medicine. 13 (8): e1002108. doi:10.1371/journal.pmed.1002108. PMC 5019340. PMID 27575375.
  25. ↑ Eberlin LS, Tibshirani RJ, Zhang J, Longacre TA, Berry GJ, Bingham DB, et al. (February 2014). "Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging". Proceedings of the National Academy of Sciences of the United States of America. 111 (7): 2436–41. Bibcode:2014PNAS..111.2436E. doi:10.1073/pnas.1400274111. PMC 3932851. PMID 24550265.
  26. ↑ King, Mary E.; Zhang, Jialing; Lin, John Q.; Garza, Kyana Y.; DeHoog, Rachel J.; Feider, Clara L.; Bensussan, Alena; Sans, Marta; Krieger, Anna; Badal, Sunil; Keating, Michael F.; Woody, Spencer; Dhingra, Sadhna J.; Yu, Wendong; Pirko, Christopher; Brahmbhatt, Kirtan A.; Van Buren, George; Fisher, William E.; Suliburk, James; Eberlin, Livia S. (13 July 2021). "Rapid diagnosis and tumor margin assessment during pancreatic cancer surgery with the MasSpec Pen technology". Proceedings of the National Academy of Sciences of the United States. 118 (28): e2104411118. Bibcode:2021PNAS..11804411K. doi:10.1073/pnas.2104411118. PMC 8285949. PMID 34260388.
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