Elastic scattering spectroscopy as an optical marker of inflammatory bowel disease activity and subtypes.

Inflammatory bowel disease (IBD) is a spectrum of disorders that leads to inflammation of the intestinal mucosa, classified clinically as ulcerative colitis (UC) or Crohn’s disease (CD). UC involves the large intestine and causes inflammation in a continuous pattern from the rectum to the cecum. CD, however, can involve the large or small intestines, generally spares the rectum, and can lead to fistulas, abscesses, and/or strictures. In the United States, it is estimated that between 1 million and 1.5 million people have IBD.1–3 There is no gold standard for classifying IBD as UC or CD, although this is crucial for prognostic and therapeutic reasons. In the majority of cases, UC can be distinguished from CD using clinical features, laboratory testing, routine white light endoscopy with associated biopsy histopathology, and radiological imaging. However, in approximately 10% to 15% of patients with disease limited to the colon, a definitive diagnosis can be difficult.4 IBD restricted to the colon that cannot be further classified as CD or UC is termed as IBD unclassified (IBD-U).5 Laboratory markers, such as fecal markers and serological antibody testing, may be used to aid in the diagnosis of IBD,6,7 and, in cases of IBD-U, to help and distinguish between IBD subtypes and identify high-risk individuals, which may have treatment implications.8,9 Although serological biomarkers alone are not useful in diagnosing IBD,10,11 they may have an adjunctive role in cases of IBD-U and in stratifying those at high-risk for disease-related complications. Optical spectroscopy has been suggested as a promising tool for the management of IBD.12–14 Fluorescence spectroscopy has been reported to differentiate normal colon from IBD ex vivo in murine models15 and to increase the detection of invisible flat intraepithelial neoplasia.16 Recently, Raman spectroscopy has been proposed as an optical biomarker for distinguishing CD from UC in vitro in ex vivo tissue samples from patients with IBD.17 Elastic scattering spectroscopy (ESS) and related reflectance spectroscopies have shown promise in vivo in the gastrointestinal tract for detecting neoplasia in the colon,18–22 dysplasia in the esophagus,21,23–27 and colitis and dysplasia in patients with IBD.18,19 ESS has also been used to distinguish pathologies in other epithelially lined hollow organs, such as the urinary bladder,28 and in cystic and solid tissues, including breast and associated lymph nodes,29,30 pancreas,31 and thyroid.32,33 ESS, mediated by application-specific fiberoptic probes with specialized optical geometries, is sensitive to the absorption spectra of major chromophores (e.g., oxy-/deoxy-hemoglobin) and, more importantly, to the scattering spectra related to micromorphological features of tissues that are in contact with the tip of the probe. ESS spectra derive from the wavelength-dependent optical scattering efficiency (and the effects of changes in the scattering angular probability) caused by optical index gradients because of cellular and subcellular structures. Thus, unlike Raman and fluorescence spectroscopy, ESS provides largely microstructural, not biochemical, information. As such, ESS is sensitive to structural features such as nuclear size, crowding, chromaticity, and chromatin granularity, as well as to mitochondrial and organellar size and density. Such features are, to varying degrees, components of a histopathological assessment. ESS, however, is a real-time, point-source measurement that senses these types of morphological changes semiquantitatively without actually rendering a microscopic image, per se. In addition, because of its inherent simplicity and miniaturizability, ESS is extremely low cost, clinically robust, and impacts procedure flow minimally, especially when integrated into standard endoscopic biopsy tools.21 In this article, we investigate whether ESS has utility as an in vivo real-time endoscopic reporter of disease activity and an optical biomarker for distinguishing CD from UC.