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Review
. 2018 Oct;23(12):1-17.
doi: 10.1117/1.JBO.23.12.121610.

Optical and x-ray technology synergies enabling diagnostic and therapeutic applications in medicine

Brian W Pogue  1 , Brian C Wilson  2
Affiliations
Review

Optical and x-ray technology synergies enabling diagnostic and therapeutic applications in medicine

Brian W Pogue et al. J Biomed Opt. 2018 Oct.

Abstract

X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are highly advanced and diversified, being ubiquitously used throughout medicine as the single largest technology sector. Both have dominant spatial localization value, achieved with optical surface scanning or x-ray internal visualization, where one often is used with the other. Therapeutic delivery can also be enhanced by their synergy, where radio-optical and optical-radio interactions can inform about dose or amplify the clinical therapeutic value. An emerging trend is the integration of nanoparticles to serve as molecular intermediates or energy transducers for imaging and therapy, requiring careful design for the interaction either by scintillation or Cherenkov light, and the nanoscale design is impacted by the choices of optical interaction mechanism. The enhancement of optical molecular sensing or sensitization of tissue using x-rays as the energy source is an important emerging field combining x-ray tissue penetration in radiation oncology with the molecular specificity and packaging of optical probes or molecular localization. The ways in which x-rays can enable optical procedures, or optics can enable x-ray procedures, provide a range of new opportunities in both diagnostic and therapeutic medicine. Taken together, these two technologies form the basis for the vast majority of diagnostics and therapeutics in use in clinical medicine.

Keywords: imaging; optics; photo medicine; radiotherapy; spectroscopy; x ray.

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Figures

Fig. 1
Fig. 1
(a) The global market sectors (US$ billion/year) for optical and x-ray biomedical technologies. (b) The attenuation mechanisms across the usable electromagnetic spectrum for water: note the steepness of absorption and scatter on either side of the red/near-infrared wavelength ranges, and the presence of high elastic scattering in this optical “window.” Medical imaging is done in each of the three areas of low attenuation, with x-ray, optical and magnetic resonance imaging techniques.
Fig. 2
Fig. 2
Illustration of approaches to enhancing the cross-over between the x-ray and optical domains.
Fig. 3
Fig. 3
X-ray diagnostic and therapy systems in 2-D and 3-D: diagnostic x-ray imaging systems are widely used in (a) 2-D and (b) 3-D imaging as well as (c) dynamic 2-D (“2.5-D”) during fluoroscopy-guided procedures. In radiotherapy, geometric precision of dose deposition is critical and (d) dose control is obtained laterally by beam collimators and (e) axially by the choice of the beam energy or particle type. Together these axial and lateral controls are used with computational treatment planning tools to optimize a dose plan (f) with a dose volume histogram that maximizes the % area of planning treatment volume while minimizing dose to organs as risk.
Fig. 4
Fig. 4
Examples of optical technologies applied to radiation medicine. (a) Patient positioning by laser lines projected onto fiducial markers. (b) Surface projector/camera systems that use stereo vision or active illumination to map 3-D surfaces for patient position verification. (c) Measurement of blood oxygenation by pulse oximeter tracking the subtle attenuation changes from arteriole fluctuations. (d) Spectroscopic measurements from hemoglobin, water, fat or scattering to quantify constituents. (e) Direct Cherenkov imaging of radiation beams on tissue to verify delivery in real time. (f) Scintillation fiber-based dosimetry for accurate quantitative measurements of radiation in situ during radiotherapy. © Institute of Physics and Engineering in Medicine. Reproduced by permission of IOP Publishing. All rights reserved.
Fig. 5
Fig. 5
Schematic of the dependence of the dominant photophysical interaction and resulting biological effects as a function of the light pulse length for a given optical energy density. Which effect is dominant also depends strongly on the localization of the optical absorber, and the specificity increases with more intraorganelle or nuclear targeting. Microlocalization and longer treatment times both generally provide superior specificity. Increasing specificity to tumor cells relative to the surrounding normal organs is key to maximizing the ‘therapeutic ratio’ of kill between tumor and normal tissue.
Fig. 6
Fig. 6
Direct and secondary x-ray (or radionuclide) interactions producing light via (a) scintillation or (b) Cherenkov. (c) Order-of-magnitude estimates of the light yields in tissue. (d) Energy dependence of the two processes.
Fig. 7
Fig. 7
X-ray interactions mediated by nanoparticles. (a) Metal nanoparticles generating direct electron emission, (b) nanoscintillators generating light that then activate photosensitizers, (c) photocatalyst mediating photoelectron and free-radical generation, and (d) direct generation of biologically active species from x-ray absorption in photosensitizers.,,,,
Fig. 8
Fig. 8
Nanoparticle modifications, going from the active core, through stabilizing coatings, biomarker targeting, catalyst, or other active layers or coupling with light- or electronically-activated sensitizers, and incorporation into microstructures.
Fig. 9
Fig. 9
Schematic of the dependence of effective photoactivation on the nanoscintillator- photosensitizer distance. (a) Resonant energy transfer at ∼<10  nm, (c) nonresonant energy transfer through light emission by the donor and subsequent absorption by the acceptor, (b) combined distance dependence, with transition region near R∼10  nm, (d) intrinsic scintillation and Cherenkov emission spectra in nearfield areas (R∼<effective attenuation distance), and (e) preferential blue/green light attenuation in tissue.
Fig. 10
Fig. 10
Examples of x-ray-mediated phototherapeutics with psoralen photosensitization by Cherenkov light. (a) Spectral overlap of Cherenkov light and psoralen absorption, relative to the UVA light used in PUVA. (b) Scintillating CeF3 nanocrystals coupled with photosensitizer (VP), with spectral overlap of the scintillation emission with the Soret band of VP, producing singlet-oxygen (O21) from collisional quenching by molecular oxygen (O2). (c) X-ray Cherenkov excitation of TiO2 nanoparticles from Cu64, producing cytotoxic photosensitization in tumor cells.
Fig. 11
Fig. 11
X-ray luminescence computed tomography. (a) Rotational geometry of a KeV x-ray source. (b) resulting sinograms and reconstructed images of NIR emission in tissue phantoms. (c) Example of in vivo planar imaging of lymph nodes using rare-earth-doped nanoscintillators at 45 min after injection.
Fig. 12
Fig. 12
Cherenkov luminescence molecular oxygen imaging. (a) Schematic of orthogonal line scanning from a 6 MV x-ray linac beam used to excite the luminescence that is captured by a time-synchronized camera. (b) Resulting reconstructed image in vivo from three orthogonal sheet scans. (c) Human body phantom with 1-D scanning, using (d) PtG4 samples on the chest cavity to simulate lymph nodes, and (e) covered with artificial skin. (f, g) Maximum-intensity projection Cherenkov and luminescence images. (h) CELSI image overlaid on the x-ray scans of the body phantom.
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