Noninvasively Imaging pH at the Surface of Implanted Orthopedic Devices with X-ray Excited Luminescence Chemical Imaging

Abstract

Implanted medical device-associated infections are a leading cause of fixation failure, and early diagnosis is the key to successful treatment. During infection, acidosis near the implant plays a role in antibiotic resistance and low pH is a potential infection indicator. Herein, we describe a pH sensor which attaches to the implants to noninvasively image local pH with high spatial resolution. The sensor has two layers: a scintillator layer which emits 620 and 700 nm light upon X-ray irradiation and a pH indicator layer containing bromocresol green dye that absorbs 620 nm luminescence in neutral/basic pH and passes 700 nm light at all pHs. We also developed a dedicated imaging system capable of scanning relatively large specimens through thick tissues. A focused X-ray beam irradiates one spot on the sensor, and the 620 to 700 nm peak ratio is measured to determine the local pH; images are acquired by scanning the X-ray beam across the surface and measuring the pH point-by-point. The sensor was covered with varying thickness slices of chicken breast tissue (0−19 mm) to evaluate how the tissue affects the peak intensity and ratio. Thick tissues attenuated both 620 and 700 nm light, with more attenuation at 620 nm than 700 nm. Although this spectral distortion shifted the pH calibration curve, the effect could be corrected for using a scintillator film region with no pH indicator layer as a spectral reference. The sensor was attached to an orthopedic plate affixed to a human cadaveric tibia and imaged through tissue. This approach provides both high spatial resolution from focused X-ray excitation and surface chemical specificity from the indicator dye, providing a tool for imaging local pH through tissue.

Review of in vivo optical molecular imaging and sensing from x-ray excitation

“…[105][106][107][108] For example, Gd 2 O 2 S∶Tb-based nanoparticles have been designed for pH-dependent sensors, for monitoring bacterial infection or as nanocapsules that carry chemotherapy. [109][110][111] Some scintillating nanomaterials in this category exhibit x-ray-excited persistent luminescence, which can still emit long-lasting phosphorescence after the x-ray irradiation is completed. 106,112,113 Other composite nanomaterials, such as quantum dots (QDs), 114 silicon nanocrystals, 115 metal-organic structures, 116 and gold nanoclusters, 117 have also been reported to emit luminescence under x-ray irradiation.…”

“…135 Then the noninvasive pH sensing was used to monitor bacterial infection and treatment of implanted medical devices through tissues after coating on implanted surfaces. 110,111 Using a pH-triggered nanocapsule, spectral changes were sensitive to the release of doxorubicin, which can be used to track drug release in the acidic tumor microenvironment. 109 Some pH-dependent long-lived emission luminescent probes appear promising for Cherenkov-based lifetime detection.…”

Conformal Coating of Orthopedic Plates with X-ray Scintillators and pH Indicators for X-ray Excited Luminescence Chemical Imaging through Tissue

“…Once cured, the samples were put in a beaker of water to dissolve the sugar and salt off the surface. These were then dried and dip coated in PEG hydrogel solution described earlier 15 at concentrations of 10%, 50%, and 80% (w/w) PEG in a water/glycerol solution containing a pH dye (either bromocresol green or bromothymol blue). A sugar (sucrose) and salt (sodium chloride) roughened epoxy sample was used for each concentration, the sample being dip coated in polymer solution under nitrogen atmosphere and cured under UV for one minute.…”

“…We developed a pH sensor read with XELCI to map the surface pH of the orthopedic devices in order to help detect and monitor implant associated infection. 5,15 In order to show the proof of concept and to characterize the sensor's luminescent signal through tissue, we previously used a 3D printed clip to attach the the sensor to the orthopedic plate. However, our ultimate goal is to develop the pH sensor into a conformal coating that can be used to cover the full surface of the orthopedic implant in order to map the surface pH of the whole implant.…”

“…5,14 We also improved our pH sensor to be more robust and biocompatible by shifting to a hydrogel based sensor and evaluated the performance by imaging it at various pH through different thicknesses of chicken tissue and human cadaveric tissue. 15 The goal in this study was to develop the pH sensor into a conformal coating which could be applied to titanium orthopedic implants eventually for studies in small animals.…”