Adam de la Zerda

Stanford University, Palo Alto, California, United States

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Publications (35)206.11 Total impact

  • Yonatan Winetraub · Elliott D. SoRelle · Orly Liba · Adam de la Zerda
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    ABSTRACT: We have developed a model to accurately quantify the signals produced by exogenous scattering agents used for contrast-enhanced Optical Coherence Tomography (OCT). This model predicts distinct concentration-dependent signal trends that arise from the underlying physics of OCT detection. Accordingly, we show that real scattering particles can be described as simplified ideal scatterers with modified scattering intensity and concentration. The relation between OCT signal and particle concentration is approximately linear at concentrations lower than 0.8 particle per imaging voxel. However, at higher concentrations, interference effects cause signal to increase with a square root dependence on the number of particles within a voxel. Finally, high particle concentrations cause enough light attenuation to saturate the detected signal. Predictions were validated by comparison with measured OCT signals from gold nanorods (GNRs) prepared in water at concentrations ranging over five orders of magnitude (50 fM to 5 nM). In addition, we validated that our model accurately predicts the signal responses of GNRs in highly heterogeneous scattering environments including whole blood and living animals. By enabling particle quantification, this work provides a valuable tool for current and future contrast-enhanced in vivo OCT studies. More generally, the model described herein may inform the interpretation of detected signals in modalities that rely on coherence-based detection or are susceptible to interference effects.
    No preview · Article · Jan 2016 · Applied Physics Letters
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    ABSTRACT: Gold nanorods (GNRs, ~50 x 15 nm) have been used ubiquitously in biomedicine for their optical properties, and many biofunctionalization methods have been described for them. Recently, the synthesis of larger-than-usual GNRs (LGNRs, ~100 x 30 nm) has been demonstrated. However, LGNRs have not been biofunctionalized and therefore remain absent from biomedical literature to date. Here we report the first biofunctionalization of LGNRs, resulting in highly stable particles with a narrow spectral peak (FWHM ~100 nm). We further demonstrated that functionalized LGNRs can be used as highly sensitive contrast agents for Optical Coherence Tomography (OCT), visualizing individual LGNRs in clear liquids. Owing to their increased optical cross-sections, we found that LGNRs exhibited up to 32-fold higher signal than conventional GNRs. We leveraged these enhanced optical properties to detect LGNRs in the vasculature of live tumor-bearing mice. Due to LGNR-enhanced OCT signal, we were able to visualize tumor blood vessels at depths that were otherwise undetectable. We expect that the particles reported herein will enable immediate sensitivity improvements for a wide array of biomedical imaging techniques that rely on conventional GNRs.
    No preview · Article · Oct 2015 · Langmuir
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    ABSTRACT: The growing use of nanoparticles in biomedical applications, including cancer diagnosis and treatment, demands the capability to exactly locate them within complex biological systems. In this work a correlative optical and scanning electron microscopy technique was developed to locate and observe multi-modal gold core nanoparticle accumulation in brain tumor models. Entire brain sections from mice containing orthotopic brain tumors injected intravenously with nanoparticles were imaged using both optical microscopy to identify the brain tumor, and scanning electron microscopy to identify the individual nanoparticles. Gold-based nanoparticles were readily identified in the scanning electron microscope using backscattered electron imaging as bright spots against a darker background. This information was then correlated to determine the exact location of the nanoparticles within the brain tissue. The nanopartides were located only in areas that contained tumor cells, and not in the surrounding healthy brain tissue. This correlative technique provides a powerful method to relate the macro- and micro-scale features visible in light microscopy with the nanoscale features resolvable in scanning electron microscopy.
    No preview · Article · Jan 2015 · Micron
  • E. SoRelle · O. Liba · Z. Hussain · M. Gambhir · A. De La Zerda
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    ABSTRACT: Nanoparticles can be synthesized in a wide array of shapes and sizes to suit specific biomedical applications in therapy and imaging. Prerequisite to such applications are particle stability in biological environments, non-toxicity, and facile conjugation of the particle surface with targeting biological moieties (such as antibodies). Here we report significant flaws in the common methods used to functionalize the surface of gold nanorods (GNRs) of larger-than-usual sizes. We find that while GNRs of sizes smaller than 50 × 15 nm can be effectively stabilized by polyethylene glycol (PEG)-based methods, larger GNRs form major aggregates and crash under similar functionalization conditions. Large GNRs may provide enhanced imaging sensitivity in biological applications due to greater optical extinction cross sections, provided that the GNRs can be made biostable. In this study, GNRs of sizes up to 90 × 30 nm were synthesized using two different published methods. Particle morphology and size distributions were characterized using Transmission Electron Microscopy (TEM), and optical spectra were measured by Vis-NIR Spectrometry. The colloidal stability of different-sized GNRs was assayed at various stages of functionalization using zeta potential and Vis-NIR measurements. The results of these experiments indicate that large GNRs functionalized with PEG undergo irreversible aggregation after minimal washing. We find that coating large GNRs with polystyrene sulfonate (PSS) instead of PEG vastly improves GNR stability in water and serum. Moreover, we provide a novel platform for conjugating biomolecules of interest to PSS-coated large GNRs. We show that larger GNRs produce stronger photoacoustic signal than commonly used smaller GNRs, indicating an advantage of using large GNRs for biomedical imaging. Our observations underscore that the biomedical advantages of novel nanoparticle synthesis methods may not be realized without tailored surface functionalization methods. More generally, our results suggest that materially-identical nanoparticles (i.e. GNRs) exhibit varying stability as a function of particle size.
    No preview · Article · Jan 2015
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    ABSTRACT: Optical Coherence Tomography (OCT) is a powerful imaging modality to visualize tissue structures, with axial image pixel resolution as high as 1.6 um in tissue. However, OCT is intrinsically limited to providing structural information as the OCT contrast is produced by optically scattering tissues. Here we demonstrate gold nanorods (GNRs) injected into the anterior chamber (AC) and cornea of mice eyes can create a significant OCT signal and hence can be used as a contrast agent for in vivo OCT imaging. We show that a low dose of 30 nM of GNRs (13 nm in diameter and 45 nm in length) injected to the AC of mice eyes produced an OCT contrast nearly 50-fold higher than control mice injected with saline. Furthermore, we experimentally estimated the lowest detectable concentration of GNRs in living mice eyes to be as low as 120 pM, representing a significant improvement over conventional optical fluorescence imaging. The high sensitivity and low toxicity of GNRs brings great promise for OCT to uniquely become a high-resolution molecular imaging modality.
    No preview · Article · Feb 2014 · Clinical and Experimental Ophthalmology
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    ABSTRACT: Glycoproteins in focus: Metabolic labeling of glycans with azido sugars in combination with two-photon fluorescence lifetime imaging microscopy enables the visualization of specific glycoforms of endogenous proteins. This method can be utilized to detect glycosylated proteins in both cell culture and intact human tissue slices.
    No preview · Article · Dec 2013 · Angewandte Chemie International Edition
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    ABSTRACT: A nanoplasmonic biosensor for highly-sensitive, single-step detection of protein biomarkers is presented. The principle is based on the utilization of the optical scattering properties of gold nanorods (GNRs) conjugated to bio-recognition molecules. The nanoplasmonic properties of the GNRs were utilized to detect proteins using near-infrared light interferometry. We show that the antibody-conjugated GNRs can specifically bind to our model analyte, Glucose Transporter-1 (Glut-1). The signal intensity of back-scattered light from the GNRs bound after incubation, correlated well to the Glut-1 concentration as per the calibration curve. The detection range using this nanoplasmonic immunoassay ranges from 10 ng/mL to 1 ug/mL for Glut-1. The minimal detectable concentration based on the lowest discernable concentration from zero is 10 ng/mL. This nanoplasmonic immunoassay can act as a simple, selective, sensitive strategy for effective disease diagnosis. It offers advantages such as wide detection range, increased speed of analysis (due to fewer incubation/washing steps), and no label development as compared to traditional immunoassay techniques. Our future goal is to incorporate this detection strategy onto a microfluidic platform to be used as a point-of-care diagnostic tool.
    Full-text · Article · Mar 2013
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    ABSTRACT: Molecular optical imaging is a widespread technique for interrogating molecular events in living subjects. However, current approaches preclude long-term, continuous measurements in awake, mobile subjects, a strategy crucial in several medical conditions. Consequently, we designed a novel, lightweight miniature biosensor for in vivo continuous optical sensing. The biosensor contains an enclosed vertical-cavity surface-emitting semiconductor laser and an adjacent pair of near-infrared optically filtered detectors. We employed two sensors (dual sensing) to simultaneously interrogate normal and diseased tumor sites. Having established the sensors are precise with phantom and in vivo studies, we performed dual, continuous sensing in tumor (human glioblastoma cells) bearing mice using the targeted molecular probe cRGD-Cy5.5, which targets αVβ3 cell surface integrins in both tumor neovasculature and tumor. The sensors capture the dynamic time-activity curve of the targeted molecular probe. The average tumor to background ratio after signal calibration for cRGD-Cy5.5 injection is approximately 2.43±0.95 at 1 h and 3.64±1.38 at 2 h (N=5 mice), consistent with data obtained with a cooled charge coupled device camera. We conclude that our novel, portable, precise biosensor can be used to evaluate both kinetics and steady state levels of molecular probes in various disease applications.
    Full-text · Article · Nov 2012 · Journal of Biomedical Optics
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    ABSTRACT: Photoacoustic imaging is a unique modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a family of novel photoacoustic contrast agents that are based on the binding of small optical dyes to single-walled carbon nanotubes (SWNT-dye). We synthesized five different SWNT-dye contrast agents using different optical dyes, creating five "flavors" of SWNT-dye nanoparticles. In particular, SWNTs that were coated with either QSY(21) (SWNT-QSY) or indocyanine green (SWNT-ICG) exhibited over 100-times higher photoacoustic contrast in living animals compared to plain SWNTs, leading to subnanomolar sensitivities. We then conjugated the SWNT-dye conjugates with cyclic Arg-Gly-Asp peptides to molecularly target the α(v)β(3) integrin, which is associated with tumor angiogenesis. Intravenous administration of these tumor-targeted imaging agents to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. Finally, we were able to spectrally separate the photoacoustic signals of SWNT-QSY and SWNT-ICG in living animals injected subcutaneously with both particles in the same location, opening the possibility for multiplexing in vivo studies.
    No preview · Article · May 2012 · ACS Nano
  • Adam de la Zerda
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    ABSTRACT: Photoacoustic imaging is a relatively new imaging modality with great promise to overcome most of the limitation of conventional optical imaging. By leveraging the conversion of short light pulses into ultrasound waves, it is possible to generate three-dimensional maps of a tissue with high spatial resolution and at a high tissue depth of penetration. Since the basic mechanism that gives rise to a photoacoustic signal is light absorption, several endogenous contrasts can be used for photoacoustic imaging of tissues, including hemoglobin and melanin. To allow photoacoustic imaging to reach its full potential, exogenous contrast agents that can target biomolecules in living tissues were developed, enabling molecular imaging studies. This chapter will review the physical basis of photoacoustic imaging, starting with the photoacoustic effect and the conditions needed to generate detectable ultrasonic waves from light excitation of an absorber. The different photoacoustic scanner implementations will then be discussed, including photoacoustic tomography (PAT) and microscopy systems and the biomedical applications to which they are best suited. Finally, the various exogenous contrast agents for photoacoustic imaging will be discussed and a general approach for contrast agent validation will be described.
    No preview · Article · May 2012
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    ABSTRACT: The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging-photoacoustic imaging-Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality-nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.
    Full-text · Article · Apr 2012 · Nature medicine
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    ABSTRACT: Molecular imaging employing optical imaging instrumentation is a widespread, robust technique for in vivo imaging in preclinical models. Nevertheless, current limitations of optical imaging instrumentation include bulky, expensive equipment, the requirements for anesthetized, immobilized subjects, limitations to deep tissue imaging and temporal resolution, and the inability to perform long term (days) continuous imaging in one field of view. To complement whole body imaging approaches, we have recently developed a novel microfabricated, implantable biosensor, consisting of a Vertical Cavity Surface Emitting Laser (VCSEL), photodetector and optical filter optimized for Cy5.5 (675 excitation, 5 nm bandwidth) excitation and emission (O’Sullivan, Parashurama et al. Optics Express 2010). Here we utilize the same miniature biosensor, housing two detectors with one as a reference, to perform continuous molecular sensing of an established molecular probe pair, cRGD-Cy5.5 (n=6) and cRAD-Cy5.5 (n=3) in U87 tumors in nude mice. After injection, continuous sensing was achieved for every 5 seconds per detector as long as six hours, and major sources of noise were replicated with a reference detector. Peak activity was measured between 700-1000s after injection for both RAD and RGD. With background subtraction, the signal to background ratio for cRGD at 30 min, 1 h, 1.5h, and 2h was 1.69 ± 0.37, 1.73 ± 0.28, 1.75 ± 0.37, and 1.83 ± 0.42, respectively (N=6). On the other hand, the signal to background ratio of cRAD at 30 min, 1 h, 1.5h, and 2h was 0.68 ± 0.20, 0.77 ± 0.20, 0.84 ± 0.27, 0.91 ± 0.27, respectively (N=3), and the differences between were statistically significant (30 min (P<0.001), 1h (P<0.001), 1.5h (P<0.002), 2h (P<0.010) and correlated well with CCD camera data. We then analyzed continuous data by performing 4 parameter curve fitting of normalized, continuous data for individual mice, comparing control sites to tumor sites. Our results quantitatively demonstrate that in certain subgroups of mice, loss of signal (probe) from tumor occurs at a different rate then loss of signal (probe) from control site. We conclude that our biosensor works in a comparable fashion to CCD camera, can be used to continuously sense dynamics of molecular probe in a disease model, can reveal individual difference between mice, and can be adapted for both as a new enabling tool in noninvasive sensing and minimally invasive sensing, in both preclinical models and potentially clinical settings.
    No preview · Conference Paper · Oct 2011
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    Preview · Dataset · Oct 2011
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    ABSTRACT: Various nanoparticles have raised significant interest over the past decades for their unique physical and optical properties and biological utilities. Here we summarize the vast applications of advanced nanoparticles with a focus on carbon nanotube (CNT)-based or CNT-catalyzed contrast agents for photoacoustic (PA) imaging, cytometry and theranostics applications based on the photothermal (PT) effect. We briefly review the safety and potential toxicity of the PA/PT contrast nanoagents, while showing how the physical properties as well as multiple biological coatings change their toxicity profiles and contrasts. We provide general guidelines needed for the validation of a new molecular imaging agent in living subjects, and exemplify these guidelines with single-walled CNTs targeted to α(v) β(3) , an integrin associated with tumor angiogenesis, and golden carbon nanotubes targeted to LYVE-1, endothelial lymphatic receptors. An extensive review of the potential applications of advanced contrast agents is provided, including imaging of static targets such as tumor angiogenesis receptors, in vivo cytometry of dynamic targets such as circulating tumor cells and nanoparticles in blood, lymph, bones and plants, methods to enhance the PA and PT effects with transient and stationary bubble conjugates, PT/PA Raman imaging and multispectral histology. Finally, theranostic applications are reviewed, including the nanophotothermolysis of individual tumor cells and bacteria with clustered nanoparticles, nanothrombolysis of blood clots, detection and purging metastasis in sentinel lymph nodes, spectral hole burning and multiplex therapy with ultrasharp rainbow nanoparticles.
    Full-text · Article · Sep 2011 · Contrast Media & Molecular Imaging
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    ABSTRACT: Photoacoustic imaging is an emerging modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high-contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a novel photoacoustic contrast agent, Indocyanine Green dye-enhanced single walled carbon nanotube (SWNT-ICG). We conjugated this contrast agent with cyclic Arg-Gly-Asp (RGD) peptides to molecularly target the alpha(v)beta(3) integrins, which are associated with tumor angiogenesis. Intravenous administration of this tumor-targeted contrast agent to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. The new contrast agent gave a markedly 300 times higher photoacoustic contrast in living tissues than previously reported SWNTs, leading to subnanomolar sensitivities. Finally, we show that the new contrast agent can detect approximately 20 times fewer cancer cells than previously reported SWNTs.
    Full-text · Article · Jun 2010 · Nano Letters
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    ABSTRACT: We developed a photoacoustic ocular imaging device and demonstrated its utility in imaging the deeper layers of the eye including the retina, choroid, and optic nerve. Using safe laser intensity, the photoacoustic system was able to visualize the blood distribution of an enucleated pig's eye and an eye of a living rabbit. Ultrasound images, which were simultaneously acquired, were overlaid on the photoacoustic images to visualize the eye's anatomy. Such a system may be used in the future for early detection and improved management of neovascular ocular diseases, including wet age-related macular degeneration and proliferative diabetic retinopathy.
    Full-text · Article · Feb 2010 · Optics Letters
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    ABSTRACT: We quantified the performance of time-domain imaging (TDI) and spectral imaging (SI) for fluorescence imaging of quantum dots (QDs) in three distinct imaging instruments: eXplore Optix (TDI, Advanced Research Technologies Inc.), Maestro (SI, CRi Inc.), and IVIS-Spectrum (SI, Caliper Life Sciences Inc.). The instruments were compared for their sensitivity in phantoms and living mice, multiplexing capabilities (ability to resolve the signal of one QD type in the presence of another), and the dependence of contrast and spatial resolution as a function of depth. In phantoms, eXplore Optix had an order of magnitude better sensitivity compared to the SI systems, detecting QD concentrations of ~40 pM in vitro. Maestro was the best instrument for multiplexing QDs. Reduction of contrast and resolution as a function of depth was smallest with eXplore Optix for depth of 2-6 mm, while other depths gave comparable results in all systems. Sensitivity experiments in living mice showed that the eXplore Optix and Maestro systems outperformed the IVIS-Spectrum. TDI was found to be an order of magnitude more sensitive than SI at the expense of speed and very limited multiplexing capabilities. For deep tissue QD imaging, TDI is most applicable for depths between 2 and 6 mm, as its contrast and resolution degrade the least at these depths.
    Full-text · Article · Dec 2009 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging
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    ABSTRACT: In this paper, we describe using a 2-D array of capacitive micromachined ultrasonic transducers (CMUTs) to perform 3-D photoacoustic and acoustic imaging. A tunable optical parametric oscillator laser system that generates nanosecond laser pulses was used to induce the photoacoustic signals. To demonstrate the feasibility of the system, 2 different phantoms were imaged. The first phantom consisted of alternating black and transparent fishing lines of 180 mum and 150 mum diameter, respectively. The second phantom comprised polyethylene tubes, embedded in chicken breast tissue, filled with liquids such as the dye indocyanine green, pig blood, and a mixture of the 2. The tubes were embedded at a depth of 0.8 cm inside the tissue and were at an overall distance of 1.8 cm from the CMUT array. Two-dimensional cross-sectional slices and 3-D volume rendered images of pulse-echo data as well as photoacoustic data are presented. The profile and beamwidths of the fishing line are analyzed and compared with a numerical simulation carried out using the Field II ultrasound simulation software. We investigated using a large aperture (64 x 64 element array) to perform photoacoustic and acoustic imaging by mechanically scanning a smaller CMUT array (16 x 16 elements). Two-dimensional transducer arrays overcome many of the limitations of a mechanically scanned system and enable volumetric imaging. Advantages of CMUT technology for photoacoustic imaging include the ease of integration with electronics, ability to fabricate large, fully populated 2-D arrays with arbitrary geometries, wide-bandwidth arrays and high-frequency arrays. A CMUT based photoacoustic system is proposed as a viable alternative to a piezoelectric transducer based photoacoustic systems.
    No preview · Article · Nov 2009 · IEEE transactions on ultrasonics, ferroelectrics, and frequency control
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    ABSTRACT: To determine the effectiveness of robotic stereotactic radiotherapy with image guidance and real-time respiratory tracking against early stage peripheral lung cancer. We treated patients with stage I non-small cell lung cancer (NSCLC) with CyberKnife and analysed their clinical characteristics and outcomes. All patients had co-morbid conditions that precluded lobectomy. The clinical target volume (CTV) included the gross tumour volume (GTV) and a 6mm margin in all directions to account for microscopic extension. The planning target volume (PTV) equalled CTV+2mm in all directions for uncertainty. Tumour motion was tracked using a combination of Synchrony and Xsight Spine tracking methods with the aid of a single gold marker implanted in the centre of the tumour, or using the newer Xsight Lung method without markers for selected tumours. A 60-67.5 Gy dose was prescribed to the 60-80% isodose line (median 65%) and given in three to five fractions. Patients were followed every 3 months for a median of 27.5 months (range 24-53 months). Of the 67 patients with NSCLC stage IA or IB treated between January 2004 and December 2008, we report the results of a cohort of 31 with peripheral stage I tumours of 0.6-71 cm(3) volume treated between January 2004 and December 2007 with total doses between 60 and 67.5 Gy in three to five fractions. The median D(max) was 88.2 Gy and the median V(95) of the PTV was 99.6% or 27.9 cm(3). No grade 3 or above toxicity was encountered. Four cases of radiation pneumonitis and one case of oesophagitis were observed. In those patients whose pre- and post-treatment results were available, no change in pulmonary function tests was observed. Actuarial local control was 93.2% for 1 year and 85.8% for up to 4.5 years. One-year overall survival was 93.6% and 83.5% for up to 4.5 years, as projected by Kaplan-Meier analyses. In this small cohort of patients with stage I peripheral NSCLC, robotic stereotactic radiotherapy seems to be a safe and obviously superior alternative to conventionally fractionated radiotherapy, with results that may be approaching those obtained with lobectomy without the associated morbidity.
    No preview · Article · Sep 2009 · Clinical Oncology
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    ABSTRACT: We present a monolithically integrated near-infrared fluorescence sensor incorporating a dielectric emission filter for in vivo applications. We successfully integrated a dielectric emission filter (OD3) onto a low-noise detector and sensed 50nM fluorescent dye concentration.
    Full-text · Conference Paper · May 2009

Publication Stats

2k Citations
206.11 Total Impact Points

Institutions

  • 2006-2015
    • Stanford University
      • • Department of Radiology
      • • Department of Structural Biology
      • • Department of Electrical Engineering
      Palo Alto, California, United States
  • 2009
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States