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In vivo X-Ray excited optical luminescence from phosphor-doped aerogel and Sylgard 184 composites
Radiation Physics and Chemistry (xxxx) xxxx–xxxx
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Radiation Physics and Chemistry journal homepage: www.elsevier.com/locate/radphyschem
In vivo X-Ray excited optical luminescence from phosphor-doped aerogel and Sylgard 184 composites ⁎
Stephen W. Allisona, , Ethan S. Bakerb, Kyle J. Lynchb, Firouzeh Sabrib a b
Emerging Measurements, Collierville, TN 38017, USA Dept. of Physics and Materials Science, University of Memphis, Memphis, TN 38152, USA
A R T I C L E I N F O
A BS T RAC T
Keywords: Aerogel Sylgard 184 Polymer Luminescence Medical imaging XEOL In vivo Thermographic phosphor
X-Ray excited optical luminescence (XEOL) is a new and noninvasive diagnostic technique suitable for in situ biochemical imaging and disease detection. The X-Ray excited optical luminescence of phosphor doping in crosslinked silica aerogel and Sylgard 184 hosts was investigated in this study. Composite silica aerogels and Sylgard 184 samples of 5%, 15%, and 50% concentrations by weight of La2O2S:Eu phosphor were prepared and inserted subcutaneously in a Sprague-Dawley rat and excited by X-Ray emission at 70 and 100 kV. A fiber optic bundle positioned within 5 mm of the sample collected the luminescence signal and conveyed it to a photomultiplier detector. The signal intensity scaled with dopant concentration. The time dependence of the predominantly red luminescence consisted of 60 cycle bursts of approximately 8 ms duration. The amplitude was modulated at about 10 Hz with a 60% depth. This indicates the time dependence of the X-Ray source. A simulation showed how to observe phosphor decay between individual burst pulses. The emission from the two types of composite samples was easily detected from the outside of the skin layer. Both Sylgard 184 and crosslinked silica aerogels are biocompatible and bio stable materials that could serve a variety of potential XEOL applications. These very strong signals imply potential for creating new In-vivo sensing applications and diagnostic tools.
1. Introduction X-Ray Excited Optical Luminescence (XEOL) is a new noninvasive spectroscopic diagnostic method that uses X-Rays to excite optical luminescence from a phosphor material that is embedded within a biomedical host of interest. In recent years such techniques have been proposed as a promising photo-physical mechanism to exploit for imaging of biomedical implants and organs, among others (Chen et al., 2011; Osakada et al., 2014). Typically, the luminescence is measured externally to the biomedical host and the emission characteristics contain vital information about the host in which the luminescent target is situated (Chen et al., 2012). The work of Chen et al. is an illustrative example (Chen et al., 2011). They fabricated a continuous phosphor layer on top of a linear array of silver strips where the strip width and spacing between strips was the same. As a small-spot X-Ray source moves across the sample, an external detector produces a periodic modulation, bright when only the phosphor is illuminated and dimmer when incident on the silver which partially attenuates the X-Ray source before exciting the phosphor layer underneath. As H2O2 that is present in the host
dissolves the silver, the modulation depth decreases. This allows the presence of H2O2 to be sensed and quantified. Carpenter et al. successfully demonstrated the ability to image Tb and Eu phosphors, both micro and nano-sized versions, in a gelatin phantom and small animal model (Carpenter et al., 2010, 2012). The differing wavelengths of the respective phosphor materials allowed for multiplexed contrast imaging. They also combined radio luminescent methodology as well as X-Ray excited luminescence. Sylgard 184 (Dow Corning) is of the Polydimethylsiloxane (PDMS) family and is an optically clear and inert material used extensively for a wide variety of studies including optical, biomedical, and aerospace applications (Sabri et al., 2013a, 2012a, 2008). The versatile nature of this family of polymers allows for fine tuning of bulk and surface properties as needed for each study and application (Fontenot et al., 2016). Another class of materials with a promising future as host material is aerogels (Leventis et al., 2002) which offers many attractive features relevant to this area of research. For aerospace, their low thermal conductivity and low density are of obvious value (Sabri et al., 2011). For biology and biomedicine, the tunable chemical, physical, and
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Corresponding author. E-mail addresses: [email protected] (S.W. Allison), [email protected] (E.S. Baker), [email protected] (K.J. Lynch), [email protected] (F. Sabri). http://dx.doi.org/10.1016/j.radphyschem.2017.01.045 Received 1 September 2016; Received in revised form 22 December 2016; Accepted 26 January 2017 0969-806X/ © 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: Allison, S.W., Radiation Physics and Chemistry (2017), http://dx.doi.org/10.1016/j.radphyschem.2017.01.045
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surface properties have great potential for in vitro and in vivo applications (Sabri et al., 2014, 2011, 2013b). For instance, as implants, they may serve as scaffolding for cell growth and confinement (Sabri et al., 2012b). The basis for what is reported here comes from our recently related work with incorporating phosphors into these materials. The authors (Sabri et al., 2014) showed that the phosphor powder when doped into Sylgard and crosslinked silica aerogels does not chemically alter it and the luminescence properties of the bare powder are preserved. The temperature dependence of the phosphor powder and doped Sylgard were the same. A subsequent effort examined optical luminescence from doped PDMS samples viewed through the dermis of a rat and excited by 405 nm light (Sabri et al., 2015). Red luminescence was readily detectible through the rat skin. The best results were for the instance where the excitation first excited the sample and then traversed the skin to an externally located detector. Next, coupons of Sylgard and aerogel with various phosphor powder concentrations were prepared and inserted underneath rat dermis. X-Ray images revealed that image contrast could be enhanced. X-Ray attenuation coefficients were obtained for 60 kV X-Rays (Allison et al., 2015). The present work reported here follows logically from these previous efforts. The primary concern here is to illustrate and quantify the visible luminescence signal levels generated by X-Rays and detectible through the rat dermis. This has not been done before for these materials. But also, in the course of the effort, additional X-Ray attenuation coefficient data for some of the Sylgard samples was acquired for 70 and 100 kV X-Rays thus supplementing the attenuation information at 60 kV in reference (Allison et al., 2015). We report here for the first time, X-Ray excited optical luminescence results for two new host materials, (1) crosslinked silica aerogel, and (2) Sylgard 184, for several phosphor loading levels. Aerogel and Sylgard 184 composite samples containing 5%, 15%, and 50% wt La2O2S:Eu were prepared and placed subcutaneously in a Sprague Dawley rat and excited to luminesce using a commercial X-Ray system. The phosphor used for this study, La2O2S: Eu, is a well-known X-Ray scintillator and is similar to other XEOL phosphors used in published studies. The emission by the 3+Eu activator consists of many spectral lines in the range of 400–700 nm. These have spectroscopic designations 5Di where i=0, 1 or 2. One of the motivations concerns exploring the possibility of XEOLbased in-vivo thermometry. The subject phosphor here can be used to measure temperature with a high degree of precision (Allison and Gillies, 1997). For more background, recent resources that survey luminescent materials for thermometry including relevant spectroscopy, signal, and error analysis are Brübach et al. (2013) regarding thermographic phosphors and Brites et al. (2016) which reviews a wide range of luminescent lanthanide materials. In addition there are other potential ways that XEOL may be exploited that attract interest. For example, Rogalskim (2016) developed a means for determining micron-scale displacement from XEOL-generated spectra. They mention possible applications such as sensing strain on orthopedic implants and tendon/ligament tears.
Fig. 1. Photographs of La2O2S:Eu-doped Sylgard (top) and aerogel (bottom).
concentration levels was synthesized and dried by means of the supercritical drying technique. Both types of samples were prepared in 4 cmx4cm custom designed aluminum molds and cut to the desired geometry after final curing and drying steps were completed. Images of the samples are shown in Fig. 1 (Allison et al., 2015). 2.2. Implant insertion The surgical procedure described here was performed on a single male Sprague-Dawley rat weighing 350 g described in detail previously (Leventis et al., 2002). Samples were inserted subcutaneously into the incision pocket created in the back of the rat, while situated on the XRay imaging table of a DuoView X-Ray imaging system (Revo Squared, GA). The samples were in full contact with the skin and were immobilized without the use of any sutures, adhesives, or staples. This study was approved by the Animal Care and Use Committee at the University of Memphis. 2.3. Excitation and luminescence detection Image clarity was assessed for several different configurations of the DuoView X-Ray's parameters. Imaging was performed using impulses from 0.8 to 5 s duration at 25 mA cathode current and 70 kV or 100 kV settings. Fig. 2 illustrates the test setup used for this study. To observe luminescence occurring from the composite Sylgard 184 and aerogel samples, the fiber-optic probe was placed approximately 2 mm above and to the side of the surface of the skin at the site of the incision. Control images were taken using only the probe and the specimen table to isolate any interference created by the X-Ray beam in the fiber optic probe and no signal was observed. The fiber optic probe consisting of a 3-meter long fiber bundle of about 78 each 200 µm diameter optical fibers collected the XEOL. The collection area was approximately 2 mm2. The bundle delivered the
2. Materials and methods 2.1. Synthesis and preparation of samples Crosslinked silica aerogel and Sylgard 184 composite samples with phosphor powder concentrations of 5, 15, and 50 wt% were prepared as described in detail previously by the authors (Allison et al., 2015). Phosphor powder lanthanum oxysulfide La2O2S: Eu, 0.1 mol% (Phosphor Technology SKL63, lot 15010) was combined with the pre-polymer and crosslinker of Sylgard 184 (Dow Corning, Midland, MI) prior to the curing stage of the two-part elastomer and outgassed and cured, as described previously (Allison et al., 2015). Similarly, using the sol-gel technique described elsewhere in detail (Allison et al., 2015), crosslinked silica aerogels containing La2O2S:Eu of different
Fig. 2. Test Setup for X-Ray Excited Optical Luminescence.
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Fig. 3. X-Ray Image at 100 kV, 5 s exposure for (a) 50% Sylgard and (b) 15% SYLGARD samples.
Fig. 4. Transmission for 100 kV X-Rays (a) 50% phosphor-doped Sylgard and (b) 15% phosphor-doped Sylgard.
luminescence to an end-on Hamamatsu photomultiplier tube (PMT) with an 8-mm diameter photocathode and 300–650 nm sensitivity for detecting the luminescence. The signal was displayed and digitized by a Tektronix 2012C oscilloscope with 1 MΩ termination. A USB connection with a laptop provided for data acquisition and analysis. The resulting data files consisted of up to 2500 data pairs. The time between each data point was 0.004 s, thus a scan of up to 10 s was possible. Both the X-Ray system and the oscilloscope were manually triggered. A verbal countdown procedure assured the oscilloscope triggered before the X-Ray machine. Because this was the first experience with XEOL and the strength of emission and efficiency of detection was unknown, initially, the emission was viewed without a filter. This allowed capture of as much of optical luminescence as possible. Later, an intervening 610 nm bandpass filter (Andover 610 FS10-25), was inserted in front of the detector to study the bright emission within that band.
approximated as incident on the sample, Io, is taken as the value just across the sample boundary. If the absorption beneath the sample changes due to bone and tissue, this can lead to error by this method. So the results should be taken only as indicative. Fig. 4a was created by zooming in on the 50% doped Sylgard sample of Fig. 3a. This image was imported into the open source image processing software Image J. The red box in Fig. 4a traverses the boundary of the sample. It is an Image J tool that allows the determination of the vertically averaged horizontal intensity profile within the box. The inset is the profile plot of gray scale value of intensity horizontally within the box. The value decreases from about 100 to 55. It corresponds to the left edge of the sample (I/Io=0.55). The increase from 40 to 88 indicates the right hand boundary of the sample (I/Io=0.45). The transmission by this approach is judged to be the average of the two, or I/Io=0.50. Similarly, Fig. 4b shows the gray scale signal values for the corresponding 15% doped Sylgard sample. The profile trace defined by the box tool in the Fig. 4b depicts greater transparency for this lower dopant concentration. The next figure depicts images for 70 kV incident X-Rays. Fig. 5a involves a 15%phosphor doped Sylgard sample and Fig. 5b clearly shows two samples of 15% and 50% respectively stacked on each other with the former sample slightly shifted to the left. The ratio of transmitted to incident light values determined from Figs. 4 and 5 are given in Table 1. From these values and sample thicknesses (L) which in all cases was 2.5 mm, an X-Ray attenuation coefficient (α), may be determined using the relation I/I 0 = e−αL . The results are also presented in Table 1 in units of 1/mm. To allow for comparison of different concentrations, α is divided by the concentration value which in this case is stated in terms of percent of phosphor doping. This absorption coefficient may be termed αPercent, which is α divided by percentage of dopant concentration. It is the absorption per mm per % of phosphor doping. It is expected that αPercent should be independent of dopant concentration. It is seen however that for both
3. Results 3.1. X-Ray images and analysis Example X-Ray images are seen in Fig. 3 for a setting of 100 kV at 5 s for a 50% phosphor-doped Sylgard 184 sample (Fig. 3a) and for a 15% doped Sylgard 184 sample (Fig. 3b). The samples measure approximately 11 mm×15 mm×3 mm. The fiber probe and its relation to the sample and the rat are also depicted. The coupon for this concentration is not completely radiopaque as the pelvic bone can be discerned underneath it. An estimate of the degree of X-Ray attenuation may be determined from the images. But it must be acknowledged that absorption by underlying bone and tissue makes the determination more difficult. The procedure here is to take the value of the image intensity on both sides of an edge or boundary of the sample image. The transmitted value through the sample is taken as the parameter I. The value 3
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Fig. 6. X-Ray Excited Luminescence from 15%-doped aerogel 2.4–3.4 s after oscilloscope triggered.
seconds after the oscilloscope is triggered as seen in Fig. 6. The photomultiplier signal rises to about 20 V and oscillates rapidly. After about 0.8 s, the X-Ray source terminates and the detected signal returns to background level. The luminescence is a series of short spikes whose amplitude is modulated periodically between 10 and 20 V. The temporal character of the X-Ray excitation responsible for this was not anticipated because the manufacturer's literature does not mention it. A subsequent search of the design of commercial X-Rays systems revealed that the output is typically driven by either a full-wave or half-wave rectified 60 Hz oscillating line current Khan and Gibbons (2014). The system used here is an example of the latter. To explore and clarify further, an even closer examination of a ¼ second section of data is provided by Fig. 7 for a representative Sylgard sample. There, a digitally generated and half-wave rectified 60 Hz signal (dark cyan) is superposed over the XEOL signal (red). Note that the plot symbols depict a measurement every 0.004 s. It can be seen clearly that the peak of the luminescence occurs at 60 Hz. The duration of each pulse from on to off is estimated at about 8 ms and likewise the spacing between pulses about 8 ms for a total period of about 1/60 s. Another feature of the luminescence is that the peak voltage in Figs. 6 and 7 ranges periodically from about 4–10V. The approximate distance between peaks is 0.1 s. The origin of this 10 cycle per second modulation of approximate 60% modulation is unknown. It seems reasonable to assume it is also a feature of X-Ray instrument's intensity time dependence. The repetitively pulsed nature of the X-Ray source suggests the viability of using decay times as an additional means to exploit X-Ray excited luminescence for sensing purposes. The radiative transitions of any phosphor are characterized by a distinctive decay rate. When excited by a sufficiently short impulse, the luminescence will persist
Fig. 5. Transmission of (a) 15% phosphor doped Sylgard and (b) Transmission of a stack of two samples, 15% and 50%, respectively, phosphor-doped SYLGARD for 70 kV XRays.
the 70 and 100 kV cases, the lower percentage samples provide a smaller value. It may be noted that for the lower percentage samples, attenuation is much less and therefore more sensitive to error. For example, the determined transmission for the 15% sample at 100 kV was 0.94. If the error were +/−0.02, the absorption coefficient doubles in changing from 0.96 to 0.92. Also, results for the 60 kV case taken from reference (Allison et al., 2015) are included in Table 1 for comparison. It is expected that attenuation should be less as X-Ray energy increases and this is what the analysis has determined. 3.2. Optical luminescence 3.2.1. Time dependence Fig. 6 shows the signal resulting for the case of the 15%-doped aerogel sample with no filter. The X-Ray source turns on at about 2 ½ Table 1 Attenuation of X-Rays.
100 kV 50%-doped Sylgard 100 kV 15%-doped Sylgard 70 kV 15%-doped Sylgard 70 kV stacked samples – 15%-doped end 70 kV stacked samples – 50%-doped end 60 kV 15% doped Sylgard (from reference (Allison et al., 2015)) 60 kV 50% doped Sylgard (reference (Allison et al., 2015))
Ratio transmitted to Incident (I/I0)
Sample Thickness L in mm
1 ⎛I⎞ α = − ln⎜ ⎟ L ⎝ Io ⎠ 1/mm
α percent 1/mm/percent
0.50 0.94 0.86 0.72 0.28
2.5 “ “ “ “
0.28 0.02 0.06 0.13 0.51
0.005 0.001 0.004 0.009 0.010 0.013–0.016 0.012–0.015
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Fig. 9. Results for aerogel no filter and aerogel and Sylgard with filter. Fig. 7. Signal from (a) 50% doped Sylgard compared with digitally generated rectified 60 cycle signal.
and 50% scaled approximately with the concentration, a factor of 3 1/3 would be expected. Given the uncertainties in fiber and sample placement, this appears reasonable. Also, signals from 50% aerogel and 50% Sylgard are shown for the case of signals filtered to pass a band centered at 610 nm. They appear to produce about the same amount of luminescence, again, within the uncertainty of placement. There are at least two implications of these results. The first is that XRay excitation is not affected by our two choices of phosphor host. The second is that the escape of luminescence is the same for both hosts. This is not to say that differences might not appear for greater host thicknesses or other phosphor materials. Overall, the signals are very strong. Fig. 10 shows results for two different measurements made successively for 5%, 15%, and 50% concentrations in Sylgard. The first measurement for a sample is designated as A and the second measurement as B. They were performed in quick succession except for a 30 min break following 15% A due to an electrical problem with the room's AC power. The purpose was to investigate repeatability. Once again the signals appear to scale with concentration and the results are reproducible.
with a characteristics decay time, τ. This decay time, for a number of phosphor materials, can be very temperature dependent. The decay time of the dominant red emission of the phosphor used in the present effort is about 400 µs (Fontenot et al., 2016). This is short relative to the pulses produced by this X-Ray source and due to that and the limited sampling rate, it was not possible to detect and discern any phase shift or persistence. However, there are phosphor materials with longer decay times. Several of these common thermographic phosphors have decay times of about 3 ms, for instance magnesium fluorogermanate doped with manganese (Mg4GeO6:Mn) and ruby powder (Brübach et al., 2013). To explore the feasibility of using longer decay phosphors, a phosphor signal model was constructed for a modelled excitation signal. It is depicted in Fig. 8. The phosphor luminescence is specified as single exponential according to I (t )=I0 exp (−t /τ ). To construct a total signal from the oscillating input, every 0.5 ms, a decay waveform is calculated using the amplitude of the X-Ray intensity value as I0. I(t) is calculated from that point in time t out to t+50 ms, for a total of one hundred data points. Then the waveforms are summed. Both plots are normalized to each other. A phase shift, Δφ, is easily evident as well as a persistence after the excitation has terminated. It appears that decay time information could be readily observed and measured using luminescent materials with decay times of this order.
4. Discussion and conclusion As anticipated, red XEOL emission from X-Ray excited doped Sylgard and aerogel is easily detected through thick rat skin. Future work will involve other phosphor materials and hosts. Samples of ZnS:Mn in Sylgard and aerogel and Mg4GeO6:Mn in Sylgard have already been fabricated and are available for the next test opportunity. Some attention may also be given to phosphors that emit further to the red and into the infrared since it is expected that the absorption and scattering by skin to be substantially less in that range. In addition to exploiting decay time methods, approaches based on relative spectral strength, that is, the ratio of two different luminescing
3.2.2. Signal level comparisons Fig. 9 shows results for several measurements with aerogel samples at 15% and 50% with no spectral filtering of the luminescence between the delivery fiber and photomultiplier detector. For each case the XRay duration setting was fixed at 0.8 s. The peak of the 50% sample is off scale. Judging that the minimum in the 10 Hz cycle, it is about 2 ½ times the 15% sample. If the output of the two aerogel samples at 15%
Fig. 8. Model of X-Ray Emission and Phosphor with a 3 ms decay time.
Fig. 10. Results for Sylgard at 5%, 15%, and 50%.
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instrumentation and applications. Rev. Sci. Instrum. 68 (7), 1–36. Allison, S.W., Baker, E.S., Lynch, K.J., Sabri, F., 2015. In vivo X-ray imaging with phosphor-doped PDMS and phosphor-doped aerogels. Int. J. Polym. Mater. Polym. Biomater. 64 (16). http://dx.doi.org/10.1080/00914037.2015.1030652. Brites C.D.S., A. Millan, L. D. Carlos; Chapter 281 Lanthanides in Luminescent Thermometry, Handbook on the Physics and Chemistry of Rare Earths, Vol. 49. 2016 ISBN: 9780444636997. Brübach, J., Pflitsch, C., Dreizler, A., Atakan, B., 2013. On surface temperature measurements with thermographic phosphors: a review. Prog. Energy Combust. Sci. 39 (1), 37–60. Carpenter, C.M., Sun, C., Pratx, G., 2010. Hybrid X-ray/optical luminescence imaging: characterization of experimental conditions. Med. Phys. 37 (8), 4011–4018. http:// dx.doi.org/10.1118/1.3457332. Carpenter, C.M., Sun, C., Pratx, G., Liu, H., Cheng, Z., Xing, L., 2012. Radioluminescent nanophosphors enable multiplexed small-animal imaging. 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Mitchell, K.E., Gardner, V., Allison, S.W., Sabri, F., 2016. Synthesis and characterization of flexible thermographic phosphor temperature sensors. Opt. Mater. 60, 50–56, (ISSN 0925-3467). Osakada, Y., Pratx, G., Sun, C., Sakamoto, M., Ahmad, M., Volotskova, O., Ong, Q., Teranishi, T., Harada, Y., Xing, L., Cui, B., 2014. Hard X-ray-induced optical luminescence via biomolecule-directed metal cluster. Chem. Commun. 50 (27), 3549–3551. http://dx.doi.org/10.1039/c3cc48661c. Rogalski, M.M., 2016. Development of Position-Dependent Luminescent Sensors: Spectral Rulers and Chemical Sensing Through Tissue (All Dissertations). Clemson University, Clemson, SC. Rogers, J.A., Someya, T., Huang, Y., 2010. Materials and mechanics for stretchable electronics. Science 327, 1603. http://dx.doi.org/10.1126/science. Sabri, F., Marchetta, J., Smith, K., 2013a. Thermal conductivity studies of a polyurea cross-linked silica aerogel-RTV 655 compound for cryogenic propellant tank applications in space. Acta Astronaut. 91, 173–179. Sabri, F., Lynch, K.J., Allison, S., 2015. Polymer-encapsulated phosphor particles for in vivo phosphor luminescence applications. Int. J. Polym. Mater. Polym. Biomater. 64 (13), 690–694. http://dx.doi.org/10.1080/00914037.2014.1002096. Sabri F., J. A. Cole, M. C. Scarbrough, N. Leventis,Investigation of crosslinked silica Aerogels for implant applications. In Biomedical Sciences and Engineering Conference (BSEC), 2011, pp. 1-3. IEEE, 2011. Sabri, F., Cole, J.A., Scarbrough, M.C., Leventis, N., 2012b. Investigation of polyureacrosslinked silica aerogels as a neuronal scaffold. A Pilot Study. http://dx.doi.org/ 10.1371/journal.pone.0033242. F. Sabri, K. Lynch, R. Wilson, and S. W. Allison, Sensing with Polymer-Doped PDMS, IET & ISA 60th International Instrumentation Symposium 2014, January 2015 page 3.1.1 London, UK 24-26 June 2014 DOI: 10.1049/cp.2014.0539. Sabri, F., Sebelik, M.E., Meacham, R., Boughter, J.D., Jr, Challis, M.J., Leventis, N., 2013b. 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states, are also viable for measuring temperature. Brites et al. (2016) state that “Temperature measurement based on intensity changes require ratiometric readout.” Thus, future plans are to investigate this approach. For the subject phosphor the ratio of 5D2 emission from the band at 510 nm to either 5D1 emission at 538 nm or 5D0 emission at 620 nm are very sensitive to temperature. The observation that signal strengths in this work are strong implies that a wide range of the spectrum will be available to overcome skin absorption as wavelengths become shorter. Thus, in vivo skin spectral transmission measurements (that is, spectral analysis of escaping light) could enable any of a variety of spectroscopy based sensor concepts. For XEOL that is sufficiently deep in the infrared, there is the possibility of sensing and quantifying the presence of substances in skin and blood. There is another implication of the ability to generate strong signals. The signal collection optics or fiber optics can be located at a greater distance away from the test zone. This could allow addition of other instrumentation and devices for other complementary purposes. An important conclusion is that the XEOL signals are sufficiently strong that the samples can be made thinner and thus more transparent to X-Rays if preservation of the X-Ray image is desired. In addition to what has been mentioned above, future efforts may be directed at quantifying the results for other X-Ray energies, currents, and durations. By properly characterizing the optical collection arrangement and using calibrated detection, it may be possible to determine XEOL efficiency for each different phosphor and host formulations. This could subsequently provide for the ability to model sensing arrangements in a laboratory environment using optical excitation. This would enable sensor development and design when an X-Ray source is not available. The Sylgard 184 tested here is an example of PDMS. PDMS is a material of interest with regard to stretchable electronics. The field owes its origin to the observation that gold naturally forms micro and nano-sized features when deposited on PDMS (Rogers et al., 2010). The present work adds to the data base of features for PDMS, its advantages and additional modes of use. Future work will involve doped spin-coated samples that 1) are thin and 2) are thin and on top of a thicker but un-doped PDMS substrate. The ability to fabricate thin samples with different dopant concentrations on top and bottom and an undoped layer between has been accomplished (Mitchell et al., 2016). Both strain and temperature measurements are viable with this material and will be explored and characterized. The results of the present work add to information regarding aerogels for its variety of uses. In conclusion, the phosphor-doped Sylgard material is an inert, bio stable host for X-Ray excited optical luminescence application development. Acknowledgements The authors would like to acknowledge Dr. Karyl Buddington for all surgical procedures that were conducted at the University of Memphis Animal Care Facility. The authors would also like to thank Dr. Randy Buddington for allowing usage of the DuoView X-Ray Detector for this study. References Allison, S.W., Gillies, G.T., 1997. Remote thermometry with thermographic phosphors:
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Radiation Physics and Chemistry journal homepage: www.elsevier.com/locate/radphyschem
In vivo X-Ray excited optical luminescence from phosphor-doped aerogel and Sylgard 184 composites ⁎
Stephen W. Allisona, , Ethan S. Bakerb, Kyle J. Lynchb, Firouzeh Sabrib a b
Emerging Measurements, Collierville, TN 38017, USA Dept. of Physics and Materials Science, University of Memphis, Memphis, TN 38152, USA
A R T I C L E I N F O
A BS T RAC T
Keywords: Aerogel Sylgard 184 Polymer Luminescence Medical imaging XEOL In vivo Thermographic phosphor
X-Ray excited optical luminescence (XEOL) is a new and noninvasive diagnostic technique suitable for in situ biochemical imaging and disease detection. The X-Ray excited optical luminescence of phosphor doping in crosslinked silica aerogel and Sylgard 184 hosts was investigated in this study. Composite silica aerogels and Sylgard 184 samples of 5%, 15%, and 50% concentrations by weight of La2O2S:Eu phosphor were prepared and inserted subcutaneously in a Sprague-Dawley rat and excited by X-Ray emission at 70 and 100 kV. A fiber optic bundle positioned within 5 mm of the sample collected the luminescence signal and conveyed it to a photomultiplier detector. The signal intensity scaled with dopant concentration. The time dependence of the predominantly red luminescence consisted of 60 cycle bursts of approximately 8 ms duration. The amplitude was modulated at about 10 Hz with a 60% depth. This indicates the time dependence of the X-Ray source. A simulation showed how to observe phosphor decay between individual burst pulses. The emission from the two types of composite samples was easily detected from the outside of the skin layer. Both Sylgard 184 and crosslinked silica aerogels are biocompatible and bio stable materials that could serve a variety of potential XEOL applications. These very strong signals imply potential for creating new In-vivo sensing applications and diagnostic tools.
1. Introduction X-Ray Excited Optical Luminescence (XEOL) is a new noninvasive spectroscopic diagnostic method that uses X-Rays to excite optical luminescence from a phosphor material that is embedded within a biomedical host of interest. In recent years such techniques have been proposed as a promising photo-physical mechanism to exploit for imaging of biomedical implants and organs, among others (Chen et al., 2011; Osakada et al., 2014). Typically, the luminescence is measured externally to the biomedical host and the emission characteristics contain vital information about the host in which the luminescent target is situated (Chen et al., 2012). The work of Chen et al. is an illustrative example (Chen et al., 2011). They fabricated a continuous phosphor layer on top of a linear array of silver strips where the strip width and spacing between strips was the same. As a small-spot X-Ray source moves across the sample, an external detector produces a periodic modulation, bright when only the phosphor is illuminated and dimmer when incident on the silver which partially attenuates the X-Ray source before exciting the phosphor layer underneath. As H2O2 that is present in the host
dissolves the silver, the modulation depth decreases. This allows the presence of H2O2 to be sensed and quantified. Carpenter et al. successfully demonstrated the ability to image Tb and Eu phosphors, both micro and nano-sized versions, in a gelatin phantom and small animal model (Carpenter et al., 2010, 2012). The differing wavelengths of the respective phosphor materials allowed for multiplexed contrast imaging. They also combined radio luminescent methodology as well as X-Ray excited luminescence. Sylgard 184 (Dow Corning) is of the Polydimethylsiloxane (PDMS) family and is an optically clear and inert material used extensively for a wide variety of studies including optical, biomedical, and aerospace applications (Sabri et al., 2013a, 2012a, 2008). The versatile nature of this family of polymers allows for fine tuning of bulk and surface properties as needed for each study and application (Fontenot et al., 2016). Another class of materials with a promising future as host material is aerogels (Leventis et al., 2002) which offers many attractive features relevant to this area of research. For aerospace, their low thermal conductivity and low density are of obvious value (Sabri et al., 2011). For biology and biomedicine, the tunable chemical, physical, and
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Corresponding author. E-mail addresses: [email protected] (S.W. Allison), [email protected] (E.S. Baker), [email protected] (K.J. Lynch), [email protected] (F. Sabri). http://dx.doi.org/10.1016/j.radphyschem.2017.01.045 Received 1 September 2016; Received in revised form 22 December 2016; Accepted 26 January 2017 0969-806X/ © 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: Allison, S.W., Radiation Physics and Chemistry (2017), http://dx.doi.org/10.1016/j.radphyschem.2017.01.045
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surface properties have great potential for in vitro and in vivo applications (Sabri et al., 2014, 2011, 2013b). For instance, as implants, they may serve as scaffolding for cell growth and confinement (Sabri et al., 2012b). The basis for what is reported here comes from our recently related work with incorporating phosphors into these materials. The authors (Sabri et al., 2014) showed that the phosphor powder when doped into Sylgard and crosslinked silica aerogels does not chemically alter it and the luminescence properties of the bare powder are preserved. The temperature dependence of the phosphor powder and doped Sylgard were the same. A subsequent effort examined optical luminescence from doped PDMS samples viewed through the dermis of a rat and excited by 405 nm light (Sabri et al., 2015). Red luminescence was readily detectible through the rat skin. The best results were for the instance where the excitation first excited the sample and then traversed the skin to an externally located detector. Next, coupons of Sylgard and aerogel with various phosphor powder concentrations were prepared and inserted underneath rat dermis. X-Ray images revealed that image contrast could be enhanced. X-Ray attenuation coefficients were obtained for 60 kV X-Rays (Allison et al., 2015). The present work reported here follows logically from these previous efforts. The primary concern here is to illustrate and quantify the visible luminescence signal levels generated by X-Rays and detectible through the rat dermis. This has not been done before for these materials. But also, in the course of the effort, additional X-Ray attenuation coefficient data for some of the Sylgard samples was acquired for 70 and 100 kV X-Rays thus supplementing the attenuation information at 60 kV in reference (Allison et al., 2015). We report here for the first time, X-Ray excited optical luminescence results for two new host materials, (1) crosslinked silica aerogel, and (2) Sylgard 184, for several phosphor loading levels. Aerogel and Sylgard 184 composite samples containing 5%, 15%, and 50% wt La2O2S:Eu were prepared and placed subcutaneously in a Sprague Dawley rat and excited to luminesce using a commercial X-Ray system. The phosphor used for this study, La2O2S: Eu, is a well-known X-Ray scintillator and is similar to other XEOL phosphors used in published studies. The emission by the 3+Eu activator consists of many spectral lines in the range of 400–700 nm. These have spectroscopic designations 5Di where i=0, 1 or 2. One of the motivations concerns exploring the possibility of XEOLbased in-vivo thermometry. The subject phosphor here can be used to measure temperature with a high degree of precision (Allison and Gillies, 1997). For more background, recent resources that survey luminescent materials for thermometry including relevant spectroscopy, signal, and error analysis are Brübach et al. (2013) regarding thermographic phosphors and Brites et al. (2016) which reviews a wide range of luminescent lanthanide materials. In addition there are other potential ways that XEOL may be exploited that attract interest. For example, Rogalskim (2016) developed a means for determining micron-scale displacement from XEOL-generated spectra. They mention possible applications such as sensing strain on orthopedic implants and tendon/ligament tears.
Fig. 1. Photographs of La2O2S:Eu-doped Sylgard (top) and aerogel (bottom).
concentration levels was synthesized and dried by means of the supercritical drying technique. Both types of samples were prepared in 4 cmx4cm custom designed aluminum molds and cut to the desired geometry after final curing and drying steps were completed. Images of the samples are shown in Fig. 1 (Allison et al., 2015). 2.2. Implant insertion The surgical procedure described here was performed on a single male Sprague-Dawley rat weighing 350 g described in detail previously (Leventis et al., 2002). Samples were inserted subcutaneously into the incision pocket created in the back of the rat, while situated on the XRay imaging table of a DuoView X-Ray imaging system (Revo Squared, GA). The samples were in full contact with the skin and were immobilized without the use of any sutures, adhesives, or staples. This study was approved by the Animal Care and Use Committee at the University of Memphis. 2.3. Excitation and luminescence detection Image clarity was assessed for several different configurations of the DuoView X-Ray's parameters. Imaging was performed using impulses from 0.8 to 5 s duration at 25 mA cathode current and 70 kV or 100 kV settings. Fig. 2 illustrates the test setup used for this study. To observe luminescence occurring from the composite Sylgard 184 and aerogel samples, the fiber-optic probe was placed approximately 2 mm above and to the side of the surface of the skin at the site of the incision. Control images were taken using only the probe and the specimen table to isolate any interference created by the X-Ray beam in the fiber optic probe and no signal was observed. The fiber optic probe consisting of a 3-meter long fiber bundle of about 78 each 200 µm diameter optical fibers collected the XEOL. The collection area was approximately 2 mm2. The bundle delivered the
2. Materials and methods 2.1. Synthesis and preparation of samples Crosslinked silica aerogel and Sylgard 184 composite samples with phosphor powder concentrations of 5, 15, and 50 wt% were prepared as described in detail previously by the authors (Allison et al., 2015). Phosphor powder lanthanum oxysulfide La2O2S: Eu, 0.1 mol% (Phosphor Technology SKL63, lot 15010) was combined with the pre-polymer and crosslinker of Sylgard 184 (Dow Corning, Midland, MI) prior to the curing stage of the two-part elastomer and outgassed and cured, as described previously (Allison et al., 2015). Similarly, using the sol-gel technique described elsewhere in detail (Allison et al., 2015), crosslinked silica aerogels containing La2O2S:Eu of different
Fig. 2. Test Setup for X-Ray Excited Optical Luminescence.
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Fig. 3. X-Ray Image at 100 kV, 5 s exposure for (a) 50% Sylgard and (b) 15% SYLGARD samples.
Fig. 4. Transmission for 100 kV X-Rays (a) 50% phosphor-doped Sylgard and (b) 15% phosphor-doped Sylgard.
luminescence to an end-on Hamamatsu photomultiplier tube (PMT) with an 8-mm diameter photocathode and 300–650 nm sensitivity for detecting the luminescence. The signal was displayed and digitized by a Tektronix 2012C oscilloscope with 1 MΩ termination. A USB connection with a laptop provided for data acquisition and analysis. The resulting data files consisted of up to 2500 data pairs. The time between each data point was 0.004 s, thus a scan of up to 10 s was possible. Both the X-Ray system and the oscilloscope were manually triggered. A verbal countdown procedure assured the oscilloscope triggered before the X-Ray machine. Because this was the first experience with XEOL and the strength of emission and efficiency of detection was unknown, initially, the emission was viewed without a filter. This allowed capture of as much of optical luminescence as possible. Later, an intervening 610 nm bandpass filter (Andover 610 FS10-25), was inserted in front of the detector to study the bright emission within that band.
approximated as incident on the sample, Io, is taken as the value just across the sample boundary. If the absorption beneath the sample changes due to bone and tissue, this can lead to error by this method. So the results should be taken only as indicative. Fig. 4a was created by zooming in on the 50% doped Sylgard sample of Fig. 3a. This image was imported into the open source image processing software Image J. The red box in Fig. 4a traverses the boundary of the sample. It is an Image J tool that allows the determination of the vertically averaged horizontal intensity profile within the box. The inset is the profile plot of gray scale value of intensity horizontally within the box. The value decreases from about 100 to 55. It corresponds to the left edge of the sample (I/Io=0.55). The increase from 40 to 88 indicates the right hand boundary of the sample (I/Io=0.45). The transmission by this approach is judged to be the average of the two, or I/Io=0.50. Similarly, Fig. 4b shows the gray scale signal values for the corresponding 15% doped Sylgard sample. The profile trace defined by the box tool in the Fig. 4b depicts greater transparency for this lower dopant concentration. The next figure depicts images for 70 kV incident X-Rays. Fig. 5a involves a 15%phosphor doped Sylgard sample and Fig. 5b clearly shows two samples of 15% and 50% respectively stacked on each other with the former sample slightly shifted to the left. The ratio of transmitted to incident light values determined from Figs. 4 and 5 are given in Table 1. From these values and sample thicknesses (L) which in all cases was 2.5 mm, an X-Ray attenuation coefficient (α), may be determined using the relation I/I 0 = e−αL . The results are also presented in Table 1 in units of 1/mm. To allow for comparison of different concentrations, α is divided by the concentration value which in this case is stated in terms of percent of phosphor doping. This absorption coefficient may be termed αPercent, which is α divided by percentage of dopant concentration. It is the absorption per mm per % of phosphor doping. It is expected that αPercent should be independent of dopant concentration. It is seen however that for both
3. Results 3.1. X-Ray images and analysis Example X-Ray images are seen in Fig. 3 for a setting of 100 kV at 5 s for a 50% phosphor-doped Sylgard 184 sample (Fig. 3a) and for a 15% doped Sylgard 184 sample (Fig. 3b). The samples measure approximately 11 mm×15 mm×3 mm. The fiber probe and its relation to the sample and the rat are also depicted. The coupon for this concentration is not completely radiopaque as the pelvic bone can be discerned underneath it. An estimate of the degree of X-Ray attenuation may be determined from the images. But it must be acknowledged that absorption by underlying bone and tissue makes the determination more difficult. The procedure here is to take the value of the image intensity on both sides of an edge or boundary of the sample image. The transmitted value through the sample is taken as the parameter I. The value 3
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Fig. 6. X-Ray Excited Luminescence from 15%-doped aerogel 2.4–3.4 s after oscilloscope triggered.
seconds after the oscilloscope is triggered as seen in Fig. 6. The photomultiplier signal rises to about 20 V and oscillates rapidly. After about 0.8 s, the X-Ray source terminates and the detected signal returns to background level. The luminescence is a series of short spikes whose amplitude is modulated periodically between 10 and 20 V. The temporal character of the X-Ray excitation responsible for this was not anticipated because the manufacturer's literature does not mention it. A subsequent search of the design of commercial X-Rays systems revealed that the output is typically driven by either a full-wave or half-wave rectified 60 Hz oscillating line current Khan and Gibbons (2014). The system used here is an example of the latter. To explore and clarify further, an even closer examination of a ¼ second section of data is provided by Fig. 7 for a representative Sylgard sample. There, a digitally generated and half-wave rectified 60 Hz signal (dark cyan) is superposed over the XEOL signal (red). Note that the plot symbols depict a measurement every 0.004 s. It can be seen clearly that the peak of the luminescence occurs at 60 Hz. The duration of each pulse from on to off is estimated at about 8 ms and likewise the spacing between pulses about 8 ms for a total period of about 1/60 s. Another feature of the luminescence is that the peak voltage in Figs. 6 and 7 ranges periodically from about 4–10V. The approximate distance between peaks is 0.1 s. The origin of this 10 cycle per second modulation of approximate 60% modulation is unknown. It seems reasonable to assume it is also a feature of X-Ray instrument's intensity time dependence. The repetitively pulsed nature of the X-Ray source suggests the viability of using decay times as an additional means to exploit X-Ray excited luminescence for sensing purposes. The radiative transitions of any phosphor are characterized by a distinctive decay rate. When excited by a sufficiently short impulse, the luminescence will persist
Fig. 5. Transmission of (a) 15% phosphor doped Sylgard and (b) Transmission of a stack of two samples, 15% and 50%, respectively, phosphor-doped SYLGARD for 70 kV XRays.
the 70 and 100 kV cases, the lower percentage samples provide a smaller value. It may be noted that for the lower percentage samples, attenuation is much less and therefore more sensitive to error. For example, the determined transmission for the 15% sample at 100 kV was 0.94. If the error were +/−0.02, the absorption coefficient doubles in changing from 0.96 to 0.92. Also, results for the 60 kV case taken from reference (Allison et al., 2015) are included in Table 1 for comparison. It is expected that attenuation should be less as X-Ray energy increases and this is what the analysis has determined. 3.2. Optical luminescence 3.2.1. Time dependence Fig. 6 shows the signal resulting for the case of the 15%-doped aerogel sample with no filter. The X-Ray source turns on at about 2 ½ Table 1 Attenuation of X-Rays.
100 kV 50%-doped Sylgard 100 kV 15%-doped Sylgard 70 kV 15%-doped Sylgard 70 kV stacked samples – 15%-doped end 70 kV stacked samples – 50%-doped end 60 kV 15% doped Sylgard (from reference (Allison et al., 2015)) 60 kV 50% doped Sylgard (reference (Allison et al., 2015))
Ratio transmitted to Incident (I/I0)
Sample Thickness L in mm
1 ⎛I⎞ α = − ln⎜ ⎟ L ⎝ Io ⎠ 1/mm
α percent 1/mm/percent
0.50 0.94 0.86 0.72 0.28
2.5 “ “ “ “
0.28 0.02 0.06 0.13 0.51
0.005 0.001 0.004 0.009 0.010 0.013–0.016 0.012–0.015
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Fig. 9. Results for aerogel no filter and aerogel and Sylgard with filter. Fig. 7. Signal from (a) 50% doped Sylgard compared with digitally generated rectified 60 cycle signal.
and 50% scaled approximately with the concentration, a factor of 3 1/3 would be expected. Given the uncertainties in fiber and sample placement, this appears reasonable. Also, signals from 50% aerogel and 50% Sylgard are shown for the case of signals filtered to pass a band centered at 610 nm. They appear to produce about the same amount of luminescence, again, within the uncertainty of placement. There are at least two implications of these results. The first is that XRay excitation is not affected by our two choices of phosphor host. The second is that the escape of luminescence is the same for both hosts. This is not to say that differences might not appear for greater host thicknesses or other phosphor materials. Overall, the signals are very strong. Fig. 10 shows results for two different measurements made successively for 5%, 15%, and 50% concentrations in Sylgard. The first measurement for a sample is designated as A and the second measurement as B. They were performed in quick succession except for a 30 min break following 15% A due to an electrical problem with the room's AC power. The purpose was to investigate repeatability. Once again the signals appear to scale with concentration and the results are reproducible.
with a characteristics decay time, τ. This decay time, for a number of phosphor materials, can be very temperature dependent. The decay time of the dominant red emission of the phosphor used in the present effort is about 400 µs (Fontenot et al., 2016). This is short relative to the pulses produced by this X-Ray source and due to that and the limited sampling rate, it was not possible to detect and discern any phase shift or persistence. However, there are phosphor materials with longer decay times. Several of these common thermographic phosphors have decay times of about 3 ms, for instance magnesium fluorogermanate doped with manganese (Mg4GeO6:Mn) and ruby powder (Brübach et al., 2013). To explore the feasibility of using longer decay phosphors, a phosphor signal model was constructed for a modelled excitation signal. It is depicted in Fig. 8. The phosphor luminescence is specified as single exponential according to I (t )=I0 exp (−t /τ ). To construct a total signal from the oscillating input, every 0.5 ms, a decay waveform is calculated using the amplitude of the X-Ray intensity value as I0. I(t) is calculated from that point in time t out to t+50 ms, for a total of one hundred data points. Then the waveforms are summed. Both plots are normalized to each other. A phase shift, Δφ, is easily evident as well as a persistence after the excitation has terminated. It appears that decay time information could be readily observed and measured using luminescent materials with decay times of this order.
4. Discussion and conclusion As anticipated, red XEOL emission from X-Ray excited doped Sylgard and aerogel is easily detected through thick rat skin. Future work will involve other phosphor materials and hosts. Samples of ZnS:Mn in Sylgard and aerogel and Mg4GeO6:Mn in Sylgard have already been fabricated and are available for the next test opportunity. Some attention may also be given to phosphors that emit further to the red and into the infrared since it is expected that the absorption and scattering by skin to be substantially less in that range. In addition to exploiting decay time methods, approaches based on relative spectral strength, that is, the ratio of two different luminescing
3.2.2. Signal level comparisons Fig. 9 shows results for several measurements with aerogel samples at 15% and 50% with no spectral filtering of the luminescence between the delivery fiber and photomultiplier detector. For each case the XRay duration setting was fixed at 0.8 s. The peak of the 50% sample is off scale. Judging that the minimum in the 10 Hz cycle, it is about 2 ½ times the 15% sample. If the output of the two aerogel samples at 15%
Fig. 8. Model of X-Ray Emission and Phosphor with a 3 ms decay time.
Fig. 10. Results for Sylgard at 5%, 15%, and 50%.
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states, are also viable for measuring temperature. Brites et al. (2016) state that “Temperature measurement based on intensity changes require ratiometric readout.” Thus, future plans are to investigate this approach. For the subject phosphor the ratio of 5D2 emission from the band at 510 nm to either 5D1 emission at 538 nm or 5D0 emission at 620 nm are very sensitive to temperature. The observation that signal strengths in this work are strong implies that a wide range of the spectrum will be available to overcome skin absorption as wavelengths become shorter. Thus, in vivo skin spectral transmission measurements (that is, spectral analysis of escaping light) could enable any of a variety of spectroscopy based sensor concepts. For XEOL that is sufficiently deep in the infrared, there is the possibility of sensing and quantifying the presence of substances in skin and blood. There is another implication of the ability to generate strong signals. The signal collection optics or fiber optics can be located at a greater distance away from the test zone. This could allow addition of other instrumentation and devices for other complementary purposes. An important conclusion is that the XEOL signals are sufficiently strong that the samples can be made thinner and thus more transparent to X-Rays if preservation of the X-Ray image is desired. In addition to what has been mentioned above, future efforts may be directed at quantifying the results for other X-Ray energies, currents, and durations. By properly characterizing the optical collection arrangement and using calibrated detection, it may be possible to determine XEOL efficiency for each different phosphor and host formulations. This could subsequently provide for the ability to model sensing arrangements in a laboratory environment using optical excitation. This would enable sensor development and design when an X-Ray source is not available. The Sylgard 184 tested here is an example of PDMS. PDMS is a material of interest with regard to stretchable electronics. The field owes its origin to the observation that gold naturally forms micro and nano-sized features when deposited on PDMS (Rogers et al., 2010). The present work adds to the data base of features for PDMS, its advantages and additional modes of use. Future work will involve doped spin-coated samples that 1) are thin and 2) are thin and on top of a thicker but un-doped PDMS substrate. The ability to fabricate thin samples with different dopant concentrations on top and bottom and an undoped layer between has been accomplished (Mitchell et al., 2016). Both strain and temperature measurements are viable with this material and will be explored and characterized. The results of the present work add to information regarding aerogels for its variety of uses. In conclusion, the phosphor-doped Sylgard material is an inert, bio stable host for X-Ray excited optical luminescence application development. Acknowledgements The authors would like to acknowledge Dr. Karyl Buddington for all surgical procedures that were conducted at the University of Memphis Animal Care Facility. The authors would also like to thank Dr. Randy Buddington for allowing usage of the DuoView X-Ray Detector for this study. References Allison, S.W., Gillies, G.T., 1997. Remote thermometry with thermographic phosphors:
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