Raman microspectroscopy as a useful new tool in understanding thoracic aortic aneurysms
Authors: John DePaolo, Scott M. Damrauer
Journal: Cell Reports Medicine (2021)

Raman spectroscopy is a well-understood technology with novel applications in both research and clinical settings. In their article, Sugiyama and colleagues apply this technology to understand thoracic aortic aneurysm development and biomarker identification.1Sugiyama K. Marzi J. Brauchle E.M. Ando M. Yamashiro Y. Ramkhelawon B. Schenke-Layland K. Yanagisawa H. Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysms.Cell Rep. Med. 2021; 2 (this issue, 100261-1–100261-13)PubMed Google Scholar Raman spectroscopy is a well-understood technology with novel applications in both research and clinical settings. In their article, Sugiyama and colleagues apply this technology to understand thoracic aortic aneurysm development and biomarker identification.1Sugiyama K. Marzi J. Brauchle E.M. Ando M. Yamashiro Y. Ramkhelawon B. Schenke-Layland K. Yanagisawa H. Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysms.Cell Rep. Med. 2021; 2 (this issue, 100261-1–100261-13)PubMed Google Scholar Thoracic aortic aneurysms (TAAs) have an incidence of 5–10 per every 100,000 person-years, with 60% involving the aortic root or ascending aorta.2Kuzmik G.A. Sang A.X. Elefteriades J.A. Natural history of thoracic aortic aneurysms.J. Vasc. Surg. 2012; 56: 565-571Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Untreated TAAs can lead to dissection and/or rupture, both of which pose immediate threat to life and carry a high mortality rate. Ascending TAAs are most often discovered incidentally with cross-sectional imaging or through screening mechanisms for high-risk patients.3Erbel R. Aboyans V. Boileau C. Bossone E. Bartolomeo R.D. Eggebrecht H. Evangelista A. Falk V. Frank H. Gaemperli O. et al.ESC Committee for Practice GuidelinesThe Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC)2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult.Eur. Heart J. 2014; 35: 2873-2926Crossref PubMed Scopus (2222) Google Scholar Despite the identification of heritable forms of TAA linked to specific genetic mutations, much of the underlying etiology of ascending aortic disease remains unknown.4Coady M.A. Davies R.R. Roberts M. Goldstein L.J. Rogalski M.J. Rizzo J.A. Hammond G.L. Kopf G.S. Elefteriades J.A. Familial patterns of thoracic aortic aneurysms.Arch. Surg. 1999; 134: 361-367Crossref PubMed Scopus (236) Google Scholar In this issue of Cell Reports Medicine, Sugiyama and colleagues report the use of Raman spectroscopy to study the cellular and molecular structure of the aortic wall in both mouse models of TAA and human TAA tissues to shed light on the underlying pathobiology of TAA.1Sugiyama K. Marzi J. Brauchle E.M. Ando M. Yamashiro Y. Ramkhelawon B. Schenke-Layland K. Yanagisawa H. Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysms.Cell Rep. Med. 2021; 2 (this issue, 100261-1–100261-13)PubMed Google Scholar Though the theory behind Raman spectroscopy is nearly 100 years old, its utility for research and clinical applicability has only recently become understood. Raman spectroscopy allows for relatively inexpensive, non-destructive analysis of biologic material with minimal sample preparation and reproducible success.5Butler H.J. Ashton L. Bird B. Cinque G. Curtis K. Dorney J. Esmonde-White K. Fullwood N.J. Gardner B. Martin-Hirsch P.L. et al.Using Raman spectroscopy to characterize biological materials.Nat. Protoc. 2016; 11: 664-687Crossref PubMed Scopus (535) Google Scholar Furthermore, Raman spectroscopy has already demonstrated clinical utility in a number of diseases, including analysis of tumor tissue in surgical oncology and neurosurgery, where it can allow for effective, in vivo determination of the tumor margins in real time, limiting the need for excessive resection of adjacent tissue.6Hollon T. Lewis S. Freudiger C.W. Sunney Xie X. Orringer D.A. Improving the accuracy of brain tumor surgery via Raman-based technology.Neurosurg. Focus. 2016; 40: E9Crossref PubMed Scopus (55) Google Scholar, 7Nijssen A. Koljenović S. Bakker Schut T.C. Caspers P.J. Puppels G.J. Towards oncological application of Raman spectroscopy.J. Biophotonics. 2009; 2: 29-36Crossref PubMed Scopus (102) Google Scholar, 8Zúñiga W.C. Jones V. Anderson S.M. Echevarria A. Miller N.L. Stashko C. Schmolze D. Cha P.D. Kothari R. Fong Y. Storrie-Lombardi M.C. Raman spectroscopy for rapid evaluation of surgical margins during breast cancer lumpectomy.Sci. Rep. 2019; 9: 14639Crossref PubMed Scopus (30) Google Scholar In the current study, Sugiyama and colleagues utilized Raman spectroscopy to identify novel spectral-based biomarkers of aneurysmal disease in vitro in Fbln5KO and Fbln4SMKO mouse models of TAA and in situ in explanted human aortic tissue.1Sugiyama K. Marzi J. Brauchle E.M. Ando M. Yamashiro Y. Ramkhelawon B. Schenke-Layland K. Yanagisawa H. Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysms.Cell Rep. Med. 2021; 2 (this issue, 100261-1–100261-13)PubMed Google Scholar The authors were able to demonstrate clear differences between the spectral components of aortic tissue from either Fbln5KO or Fbln4SMKO mice and wild-type controls, as well as differences in ascending and descending aortic samples in the Fbln4SMKO mutant mice. Further analysis led to identification of disease-specific collagen and elastic elements in the mouse models of aortic disease. These findings were supported by the examination of human aortic tissue samples where at least one elastic and collagen element was identified as elevated among aneurysmal samples when compared to healthy human control samples. This demonstrates the potential use of Raman spectroscopy for detailed molecular characterization of aortic tissue and potentially for clinical diagnostic use. Aside from allowing detailed molecular analysis of in vivo and in situ tissues, as demonstrated in the current article, Raman spectroscopy has previously been demonstrated to allow for detailed studies of cell-state transitions with single-cell resolution.9Hsu C.C. Xu J. Brinkhof B. Wang H. Cui Z. Huang W.E. Ye H. A single-cell Raman-based platform to identify developmental stages of human pluripotent stem cell-derived neurons.Proc. Natl. Acad. Sci. USA. 2020; 117: 18412-18423Crossref PubMed Scopus (18) Google Scholar Hsu et al. were able to characterize biochemical profiles of different lineages from human-induced pluripotent stem cells and identify neural differentiation biomarkers using Raman spectroscopy to provide a better understanding of this transition as well as formulate a mechanism for quality control of neural stem cell selection for treatment applications. Using the targets identified in the current report, further investigation into the changes that aortic cells and the associated extracellular matrix proteins undergo during disease progression has the potential to create improved understanding of the dynamic cellular events involved in aneurysm pathogenesis. Raman spectroscopy has also been used to study DNA methylation patterns in human cancer cells and murine stem cells.10Daum R. Brauchle E.M. Berrio D.A.C. Jurkowski T.P. Schenke-Layland K. Non-invasive detection of DNA methylation states in carcinoma and pluripotent stem cells using Raman microspectroscopy and imaging.Sci. Rep. 2019; 9: 7014Crossref PubMed Scopus (11) Google Scholar In their study, Daum et al. were able to utilize Raman spectroscopy to characterize high and low methylation states in different cell types, suggesting a mechanism of analysis and tracking of DNA conformation over time. Methylation changes can alter the cellular transcriptome in response to environmental stimuli, leading to large changes in global patterns of gene expression. The ability to study these changes in response to alterations in aortic hemodynamics and sheer stress that occur in healthy and aneurysmal aortas may lend additional insight into the pathogenesis of TAA and identify novel pathways that could be potential targets for therapeutic manipulation. Finally, the authors identify possible in vivo clinical utility of Raman spectroscopy. Though there are diseases and procedures, such as cancer resection, where Raman spectroscopy already offers a clear benefit, the current risk of in vivo aortic analysis in humans appears to outweigh any possible benefit. However, as technology continues to evolve, allowing for improved, less invasive testing in all areas of medicine, it is conceivable to imagine these changes allowing for Raman spectroscopy to be a part of aortic surveillance for aneurysmal disease in the future, in particular if endovascular probes are developed that would allow for less-invasive analysis of the human aorta. S.M.D. is supported by the US Department of Veterans Affaris award #IK2-CX001780. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs, both outside the scope of the current manuscript. Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysmsSugiyama et al.Cell Reports MedicineApril 28, 2021In BriefSugiyama et al. performed label-free Raman imaging of human and murine ascending thoracic aortic aneurysms (aTAAs). Using Raman spectra for multivariate data analysis, they identify spectral biomarkers for aTAA in elastic fibers and collagen fibers, Ce1, and Cc6, respectively, that are significantly increased in aTAA lesions. Full-Text PDF Open Access