Noah Giese (Presenter)
University of Texas at Austin
Bio: Noah Giese is a Research Engineer at the University of Texas at Austin. He completed his Bachelor's of Science there and has been working on the MasSpec Pen with Dr. Livia Eberlin. He is interested in medicine, chemistry, and biomedical devices for clinical analysis.
Authorship: Noah Giese1, Jialing Zhang1, Nitesh Katta2, Marta Sans1, Clara Feider1, Thomas Milner2, and Livia S. Eberlin1
1 Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712 2 Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712
| Short Abstract We describe the design and development of the MasSpec Pen for use in laparoscopic and robotic surgery. We have recently reported the development of the MasSpec Pen, a handheld device that allows non-destructive molecular analysis of tissue samples. The Laparoscopic MasSpec Pen allows comparable acquisition of molecular information from tissues while operating at extended lengths and increased resolution suitable for minimally invasive surgeries. We plan to apply this technology for accurate cancer prediction from normal and tumorous human tissue. Our results provide preliminary evidence that the laparoscopic MasSpec Pen will be suitable for minimally invasive surgical procedures. |
Long Abstract
Introduction
Academic research and medicine create opportunities for advancing new technology and innovation. Medical devices are often the result of this effort, utilizing science to better human health. Currently, a surgeon and a pathologist subjectively determine surgical margins, but new technologies are being developed for margin evaluation in surgical applications. For example, spectroscopy techniques such as the Margin Probe by Dune Medical Devices uses radio frequency (RF) spectroscopy to differentiate between cancerous and normal cells using their electrical and electromagnetic properties [1]. Mass spectrometry (MS), and in particular ambient ionization approaches, offers the opportunity to introduce rich molecular information into clinical decision-making, and have shown exceptional potential for clinical use [2-3]. The development MS devices for in vivo analysis, such as the iKnife and the SpiderMass approaches, have demonstrated the application of MS in the surgical field [4]. However, new developments to couple emerging technologies to various types of surgical approaches are needed to expand their impact and use in the clinic.
We have recently developed the MasSpec Pen as a cancer detection device for intraoperative surgical diagnosis. The MasSpec Pen was applied for the diagnosis of 253 human samples, with an overall sensitivity of 96.4%, specificity of 96.2%, and accuracy of 96.3% for cancer [5]. Our vision is to use the MasSpec Pen in vivo for open surgery and ex vivo in various clinical, industrial, and research applications. Importantly, integration of the MasSpec Pen into laparoscopic and robotic surgical systems for minimally invasive procedures will facilitate its inclusion in clinical workflows. Here, we describe the development of a laparoscopic version of the MasSpec Pen featuring higher resolution of the pentip, extended length, and improved compactness for use in minimally invasive surgeries. We show that the Laparoscopic MasSpec Pen can be encapsulated in a 3mm or 4mm polytetrafluoroethylene (PTFE) tubing or Teflon, and is robust and comparable in performance to the handheld MasSpec Pen device. We demonstrate that these catheters can be utilized in 5mm and 10mm cannulas for laparoscopic surgeries and robotic manipulation such as da Vinci surgical system. We have tested the device using fresh mouse brain to demonstrate a comparable performance of the Laparoscopic MasSpec Pen to the MasSpec Pen for ex vivo analysis. Finally, we present the results of the Laparoscopic MasSpec Pen in simulated surgical use using ovarian and breast tissues from an independent set new to our classifier.
Methods
Two different diameters of laparoscopic MasSpec Pen were created using 3mm and 4mm diameter PTFE tubing (ID: 1.5mm, OD 3mm and ID: 2mm, OD 4mm). Inside these conduits, two smaller PTFE tubing (ID: 0.3mm, OD: 0.76mm) were grafted to their interior. A thin sliver of silicone tubing was applied at the terminal end extending the conduit by ~1mm creating a negative space. PTFE and silicone tubing was purchased from Cole Parmer (Vernon Hills, IL). In addition, pentips with resolution of 1.0mm, 1.2mm, and 1.5mm were manufactured with the elastomer polydimethylsiloxane (Dow Corning) using a model created by a 3D printer (Stratasys uPrint SE Plus). This entire system was inserted into an endoscopic simulation dummy via two trocar systems: a 5mm 600-428 Jarit surgical endoscopic trocar (Hawthorne, NY) or a 10mm HiCap 30107 H5 trocar by Karl Storz, (Tuttlingen, Germany).
High purity water was used for its biocompatibility with human tissue and its established role in surgical procedures. Water droplets were dispensed at the tissue surface and allowed to diffuse for three seconds. Experiments were performed on a Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Fisher Scientific). Full scan was carried out at the range of m/z 120 to 1800, using a resolving power of 140,000, and a capillary temperature of 350°C. Data was collected as the average of three consecutive scans demonstrating the highest total ion count. Mass spectra were analyzed using MSI reader and processed using R data packages.
Results
The new design of the Laparoscopic MasSpec Pen provides the formation of a water droplet that interacts with tissue to absorb cellular lipids, small molecules, and metabolites; a process that is similar to the handheld MasSpec Pen. Further, the Laparoscopic MasSpec pen was able to transport extracted lipids from the terminal end of the tubing to the mass spectrometer in a total average time of 10 seconds, which is comparable to the handheld MasSpec Pen, which samples and returns a diagnosis in less than 10 seconds. Therefore, the total time of analysis for the Laparoscopic MasSpec Pen was 15-17 seconds. These results demonstrate a comparable performance, in terms of speed and mass spectra quality, between the laparoscopic version and the original handheld design.
Fresh mouse brain was analyzed with the Laparoscopic MasSpec Pen using different tubing lengths. High relative abundances at of multiple phosphoinositide lipids, specifically glycerophosphoserine (PS 40:6) at m/z 834.531, and glycerophosphoinositol (PI 38:4) at m/z 885.553, were observed from the collected mass spectra. We also tentatively assigned m/z 888.627 as glycerophosphocholine (PC 41:3) or glycerophosphoethanolamine (PE 44:3). White matter regions from mouse brain tissue sections were analyzed to evaluate performance and reproducibility. Utilizing a 4mm PTFE tubing with a length of 4.5 meters, reproducible mass spectra were obtained with high relative abundances for m/z 885.553 and m/z 834.531. Consistent ratios between m/z 885.553 and m/z 834.531 were observed, with an RSD value of 31.7% (n=5). Other designs were tested, including a smaller sized tubing (3mm), as well as a shorter tubing length (1 meter) also providing rich molecular profiles characteristic of brain white matter regions.
Current efforts will include the application of the Laparoscopic MasSpec Pen for cancer prediction of breast and ovarian cancerous tissue unknown to our previously reported statistical classifier [5-6]. Overall accuracy, sensitivity, and specificity values will be evaluated for cancer detection, improving the robustness of our statistical classifier and demonstrating the potential of the Laparoscopic MasSpec Pen for in vivo cancer diagnosis.
Conclusions & Discussion
The objective of this project is to advance the development of MasSpec Pen into a compact, encapsulated, and self-reliant laparoscopic system that can assist surgeons during oncological resection via laparoscopic procedures and robotic assistance. The length of the tubing that transports the droplet to the mass spectrometer was extended to facilitate use in the clinical workspace. Comparable performance for lipid analysis from mouse brain tissue sections was observed from the Laparoscopic MasSpec Pen, showing consistent ratios between ions at m/z 834 and m/z 885 (RSD=31.7%, n=5). The device is engineered to be compatible with current surgical technology and future work will include its optimization for continuous analysis. We have demonstrated that the Laparoscopic MasSpec Pen maintains a quick time of analysis, is biocompatible, easy to use, and nondestructive. We envision that the Laparoscopic MasSpec Pen will enhance oncological surgical resection procedures.
References & Acknowledgements:
1. Schnabel, F.; Boolbol, S. K.; Gittleman, M.; Karni, T.; Tafra, L.; Feldman, S.; Police, A.; Friedman, N. B.; Karlan, S.; Holmes, D.; Willey, S. C.; Carmon, M.; Fernandez, K.; Akbari, S.; Harness, J.; Guerra, L.; Frazier, T.; Lane, K.; Simmons, R. M.; Estabrook, A.; Allweis, T. Annals of Surgical Oncology. 2014, 21 (5), 1589–1595.
2. J. Zhang, W. Yu, J. Suliburk, and L.S. Eberlin, “Will ambient ionization mass spectrometry become an integral technology in the operating room of the future?”, Clinical Chemistry, 2016, 62, 1172-1174.
3. D. R. Ifa, L. S. Eberlin, Ambient ionization mass spectrometry for cancer diagnosis and surgical margin evaluation. Clin. Chem. 2016, 62, 111–123.
4. J. Balog, L. Sasi-Szabó, J. Kinross, M. R. Lewis, L. J. Muirhead, K. Veselkov, R. Mirnezami, B. Dezso, L. Damjanovich, A. Darzi, J. K. Nicholson, Z. Takáts, Intraoperative tissue identification using rapid evaporative ionization mass spectrometry. Sci. Transl. Med. 2013, 5, 194ra93.
5. J. Zhang, J. Rector, J. Q. Lin, J. H. Young, M. Sans, N. Katta, N. Giese, W. Yu, C. Nagi, J. Suliburk, J. Liu, A. Bensussan, R. J. DeHoog, K. Y. Garza, B. Ludolph, A. G. Sorace, A. Syed, A. Zahedivash, T. E. Milner, L. S. Eberlin, Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Sci. Transl. Med. 2017, 9, eaan3968.
6. M. Sans, K. Gharpure, R. Tibshirani, J. Zhang, L. Liang, J. Liu, J. H. Young, R. L. Dood, A. K. Sood, L. S. Eberlin, Metabolic markers and statistical prediction of serous ovarian cancer aggressiveness by ambient ionization mass spectrometry imaging. Cancer Res. 2017, 77, 2903–2913.
This work was supported by the National Cancer Institute of the National Institutes of Health under award R00CA190783 (to L.S.E.) and the startup funds provided to L.S.E. by the University of Texas at Austin. We thank the Eberlin and Milner laboratory members for valuable discussions.
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