We describe a material that allows for high spatial resolution pH mapping through tissue using X-ray excited luminescence chemical imaging (XELCI). This is especially useful for detecting implant associated infection and elucidating how the local biochemical environment changes during infection and treatment. To acquire one pixel in the image, a focused X-ray beam irradiates a small region of scintillators coated on the implant and the X-ray excited optical luminescence spectrum is modulated by indicator dyes to provide a chemically sensitive measurement with low background. Scanning the X-ray beam across the implant surface generates high spatial resolution chemical measurements. Two associated challenges are 1) to make robust sensors that can be implanted in tissue to measure local chemical concentrations and specifically for metal orthopedic implants, and 2) to conformally coat the implant surface with scintillators and pH indicator dyes in order to make measurements over a large area. Previously, we have physically pressed or glued a pH-sensitive hydrogel sensor to the surface of an implant, but this is impractical for imaging over large irregular device areas such as an orthopedic plate with holes and edges. Herein we describe a chemically sensitive and biocompatible XELI sensor material containing scintillator particles (Gd 2 O 2 S:Eu) and a pH sensitive hydrogel coating using a roughened epoxy coating. A two-part commercial grade epoxy film was tested and found to make the coating of pH sensitive layer adhere better to the titanium surface. Sugar and salt particles were added to the surface of the epoxy as it cured to create a roughened surface and increase surface area. On this roughened surface, a secondary layer of diacrylated polyethylene glycol (PEG) hydrogel, containing a pH sensitive dye, was polymerized. This layer was found to adhere well to the epoxy-coated implant unlike other previously tested polymer surfaces which delaminated when exposed to water or humidity. The focused X-ray beam enabled 0.5 mm spatial resolution through 1 cm thick tissue. The pH sensor coated orthopedic plate was imaged with XELCI through tissue with different pH to acquire a calibration curve. The plates were also imaged through tissue with low pH region from a Staphylococcus aureus biofilm grown on one section. These studies demonstrate the use of pH sensor coated orthopedic plates for mapping the surface pH through tissue during biofilm formation using XELCI.
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. Significance: The ability to detect and localize specific molecules through tissue is important for elucidating the molecular basis of disease and treatment. Unfortunately, most current molecular imaging tools in tissue either lack high spatial resolution (e.g., diffuse optical fluorescence tomography or positron emission tomography) or lack molecular sensitivity (e.g., micro-computed tomography, ). X-ray luminescence imaging emerged about 10 years ago to address this issue by combining the molecular sensitivity of optical probes with the high spatial resolution of x-ray imaging through tissue. In particular, x-ray luminescence computed tomography (XLCT) has been demonstrated as a powerful technique for the high-resolution imaging of deeply embedded contrast agents in three dimensions (3D) for small-animal imaging. Aim: To facilitate the translation of XLCT for small-animal imaging, we have designed and built a small-animal dedicated focused x-ray luminescence tomography (FXLT) scanner with a scanner, synthesized bright and biocompatible nanophosphors as contrast agents, and have developed a deep-learning-based reconstruction algorithm. Approach: The proposed FXLT imaging system was designed using computer-aided design software and built according to specifications. nanophosphors doped with europium or terbium were synthesized with a silica shell for increased biocompatibility and functionalized with biotin. A deep-learning-based XLCT image reconstruction was also developed based on the residual neural network as a data synthesis method of projection views from few-view data to enhance the reconstructed image quality. Results: We have built the FXLT scanner for small-animal imaging based on a rotational gantry. With all major imaging components mounted, the motor controlling the gantry can be used to rotate the system with a high accuracy. The synthesized nanophosphors displayed distinct x-ray luminescence emission, which enables multi-color imaging, and has successfully been bound to streptavidin-coated substrates. Lastly, numerical simulations using the proposed deep-learning-based reconstruction algorithm has demonstrated a clear enhancement in the reconstructed image quality. Conclusions: The designed FXLT scanner, synthesized nanophosphors, and deep-learning-based reconstruction algorithm show great potential for the high-resolution molecular imaging of small animals.
Imaging probes are an important consideration for any type of contrast agent-based imaging method. X-ray luminescence imaging (XLI) and x-ray luminescence computed tomography (XLCT) are both contrast agent-based imaging methods that employ x-ray excitable scintillating imaging probes that emit light to be measured for optical imaging. In this work, we compared the performance of several select imaging probes, both commercial and self-synthesized, for application in XLI/XLCT imaging. Commercially available cadmium telluride quantum dots (CdTe QDs) and europium-doped gadolinium oxysulfide (GOS:Eu) microphosphor as well as synthesized N a G d F 4 nanophosphors doped with either europium or terbium were compared through their x-ray luminescence emission spectra, luminescence intensity, and also by performing XLCT scans using phantoms embedded with each of the imaging probes. Each imaging probe displayed a unique emission spectrum that was ideal for deep-tissue optical imaging. In terms of luminescence intensity, due to the large particle size, GOS:Eu had the brightest emission, followed by N a G d F 4 : T b , N a G d F 4 : E u , and finally the CdTe QDs. Lastly, XLCT scans showed that each imaging probe could be reconstructed with good shape and location accuracy.
Hybrid gold-polyester nanoparticles were synthesized by UV irradiation of a gold salt and photoinitiator encapsulated in a polyester nanoparticle. The resulting materials exhibit excellent cellular imaging and surface plasmon resonance properties.
We report the finding that C. elegans display X-ray avoidance behavior at high but well tolerated doses, and that this behavior appears to require LITE-1, a gustatory receptor that has been implicated in UV avoidance behavior. We recorded acute behavioral responses of wild-type worms to increasing intensities of Xray stimulation and found a positive stimulation-response relationship. Mutant strains of worms with dysfunctional photoreceptor proteins LITE-1 and GUR-3 were assayed, and the X-ray avoidance response was found to be nearly absent in LITE-1 mutants but not GUR-3 mutants, suggesting a prominent role for LITE-1 in the detection of X-rays. These findings may be important for developing optogenetics tools to stimulate cells in deep tissue using X-rays, for understanding the mechanism of LITE-1 signaling, and for understanding how organisms may respond to radiation. C. elegans | x-ray | optogenetics | LITE-1
We synthesized and characterized Eu and Tb doped NaGdF4 nanophosphors which generate visible light when excited by a focused X-ray beam. High resolution images were acquired through tissue by measuring light intensity vs. X-ray beam position.
The optical and chemical properties of gold and silver nanoparticles make them useful for many applications, including surface enhanced spectroscopy-based biosensors, photostable colorants, enhanced photovoltaic, and nanoscale optical elements. We report a simple technique to generate patterns of gold and silver nanoparticles with controlled shape and shape-dependent optical properties using metal stamps to impress them onto a glass substrate or flexible polymers. The pressure flattens the nanoparticles, converting initially spherical nanoparticles into discs with reduced height and increased diameter. This deformation causes their localized surface plasmon resonance wavelength to red-shift. Nanoparticles were characterized by electron microscopy, atomic force microscopy, and dark field optical scattering spectroscopy. The deformed nanoparticle patterns had a lateral resolution limited by the nanoparticle diameter (single particles are partly flattened only where they contact the stamp). The method also (i) transfers the stamp's topography, with smooth stamps generating flattened nanoparticles with uniform height, and small changes in stamp height are evident in the nanoparticle height and scattering wavelength, and (ii) allows facile removal of undeformed nanoparticles using scotch tape, and patterns of deformed nanoparticles can be transferred to a flexible polymer film.
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