Like all techniques that strive to bridge the gap between laboratory science and clinical medicine, electron spin resonance (ESR) spectroscopy builds on established applications in biochemistry and chemistry, following on from its discovery by Professor EK Zavoisky and colleagues in 1944 at Kazan State University, situated deep within the Tatarstan Republic of the Russian Federation, formerly the Soviet Union.¹ However, it is only now that developments in technology may perhaps allow the endoscopist of the future to acquire information on gut mucosal integrity in vivo during a procedure. This is an intriguing prospect, although there are a number of practical problems to be solved before the in vivo clinical potential of this sensitive and specific technology is realised. The average endoscopist, faced with the clinical burden of disease and an ever growing case load, requires an emerging clinical technique to robustly deliver reproducible clinically relevant data without obfuscation by artefact. The questions therefore arise of how feasible will it be for ESR spectroscopy to be implemented in the clinical arena and what additional information can be given to the average busy gastroenterologist?

To delve into the basic physics of the technique for a moment, ESR, also known as electron paramagnetic resonance (EPR) spectroscopy, describes the resonant absorption of microwave radiation by paramagnetic materials—that is to say, materials with an unpaired electron such as free radicals and transition metal ions—in the presence of a static magnetic field. Specifically, with respect to in vitro ESR spectroscopy, which is a well used biochemical tool, the sample is placed in a resonant chamber in a magnetic field and microwave frequency is then applied. The resulting ESR spectrum illustrates net absorption of microwaves at a specific frequency, which is dependent on the atomic and molecular structure of the sample under analysis. While an individual electron spin contributes to the magnetic moment of an atom, the majority of materials are not amenable to study by ESR spectroscopy as their electrons are paired and there is therefore no net bulk magnetism. This means that the region under scrutiny must contain a paramagnetic substance and so, for clinical applications, either a free radical must be administered or a so called “spin trap” must be utilised to provide a mechanism for detection of reactive naturally occurring free radicals, present only in very low concentrations.^2,3 By way of comparison, nuclear magnetic resonance (NMR) spectroscopy is based on the property of nuclear spin and there are a number of similarities between these two non-invasive techniques.^4,5 Owing to the fact that electrons have a greater magnetic moment than nuclei, ESR spectroscopy is more sensitive than NMR spectroscopy. ESR spectroscopy also has the advantage of being highly specific, although it clearly can be a disadvantage that most chemical and biological materials are not paramagnetic. ESR spectroscopy has the scope for studying faster dynamics than NMR spectroscopy as the ESR timescale in the time domain is nanoseconds and not milliseconds as in NMR.⁶ The ESR technique has more recently been harnessed to study the presence and generation of free radicals in intact cells, perfused organs, and in small animals in vivo.^7–10 For practical purposes, ESR spectroscopy allows some insight into tissue inflammation through measurement of free radicals. Taken to its logical conclusions in the clinical context, an endoscope with ESR spectroscopy capabilities could, for example, be of use for surveillance when the mucosal surface may otherwise appear normal.

In this issue of Gut, Togashi and colleagues¹¹ have used ESR spectroscopy to investigate changes in mucosal sulfhydryl compounds in an animal model of colitis [see page 1291]. These authors have previously evaluated the ESR active compound 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (carbamoyl-PROXYL) as a “spin probe” for measuring oxidative stress in the murine liver.^10,12 The same technique has been extended to experimental colitis as it was argued that adequate levels of mucosal sulfhydryl compounds, such as reduced glutathione, are critical in the prevention of tissue damage from the generation of reactive oxygen species in inflammatory conditions, such as ulcerative colitis.¹¹ This technique provides a non-destructive method of assessing oxidative stress in small animals and these authors have produced a very elegant study using their in house, low frequency, 700 MHz microwave ESR spectroscopy apparatus. The authors are developing new ESR spectroscopy equipment with a surface coil-type resonator, which may be applicable to clinical colonoscopy.

The development of low frequency ESR spectroscopy, combined with the introduction of surface coil-type resonators, has opened up a wide range of applications for ESR as the depth sensitivity of the technique has improved and the required sample size is less restricted by the dimensions of the resonator.^13,14 Furthermore, methods of reducing artefacts from voluntary and involuntary motion are being addressed.¹⁵ As with all new techniques, safety issues must be considered as magnetic fields and microwave power are integral to the ESR spectrometer, albeit at low levels, and because paramagnetic materials may be administered. The current generation of ESR spectrometers have quite limited physical space, as illustrated in the equipment used in the study of Togashi and colleagues,¹¹ and therefore larger magnets are required for interventional clinical applications. With regard to the development time to clinical usage, there are some parallels with NMR spectroscopy. The NMR phenomenon itself was discovered shortly after World War II, but it was not until the mid-1980s that human NMR spectroscopy studies started on liver and in muscle using whole body magnets.^16,17 In that sense, NMR spectroscopy was ahead of the game compared with ESR spectroscopy but there were still many years of proving the value of NMR spectroscopy before clinical studies were undertaken in earnest.^18,19 In fact, for gastroenterologists, the liver remains the main focus of interest for NMR spectroscopy as in vivo studies on the gut are fraught with technical difficulties whereas the liver as a solid organ is a much easier focus for NMR study.^20,21 Therefore, having an endoscope with in built NMR spectroscopy capabilities is still on the drawing board, rather than being a practical reality.

Returning to the problem in hand, the study by Togashi et al illustrates that it could be very desirable to have ESR spectroscopy capabilities for a new generation of future endoscopes in order to assess the mucosal integrity of the colon non-invasively in the otherwise normal looking colon of patients with quiescent colitis. However, so that this goal can become a reality, a range of safety and practical issues need to be overcome, obviously initially in the domain of research institutes where clinician scientists can conduct small scale research studies on selected patients with specialist equipment. While there are some potential pitfalls, we do suggest that you follow the development of clinical ESR spectroscopy enthusiastically. Nevertheless, it remains to say that time will tell whether the technique becomes sufficiently robust to join the diagnostic armamentarium of the busy clinical gastroenterologist.