Exposure to electromagnetic radiation can have a profound impact on human health. Ultraviolet (UV) radiation from the sun causes skin cancer. Blue light affects the body's circadian melatonin rhythm. At the same time, electromagnetic radiation in controlled quantities has beneficial use. UV light treats various inflammatory skin conditions, and blue light phototherapy is the standard of care for neonatal jaundice. Although quantitative measurements of exposure in these contexts are important, current systems have limited applicability outside of laboratories because of an unfavorable set of factors in bulk, weight, cost, and accuracy. We present optical metrology approaches, optoelectronic designs, and wireless modes of operation that serve as the basis for miniature, low-cost, and battery-free devices for precise dosimetry at multiple wavelengths. These platforms use a system on a chip with near-field communication functionality, a radio frequency antenna, photodiodes, supercapacitors, and a transistor to exploit a continuous accumulation mechanism for measurement. Experimental and computational studies of the individual components, the collective systems, and the performance parameters highlight the operating principles and design considerations. Evaluations on human participants monitored solar UV exposure during outdoor activities, captured instantaneous and cumulative exposure during blue light phototherapy in neonatal intensive care units, and tracked light illumination for seasonal affective disorder phototherapy. Versatile applications of this dosimetry platform provide means for consumers and medical providers to modulate light exposure across the electromagnetic spectrum in a way that can both reduce risks in the context of excessive exposure and optimize benefits in the context of phototherapy.

Excessive ultraviolet (UV) radiation induces acute and chronic effects on the skin, eye and immune system. Personalized monitoring of UV radiation is thus paramount to measure the extent of personal sun exposure, which could vary with environment, lifestyle, and sunscreen use. Here, we demonstrate an ultralow modulus, stretchable, skin-mounted UV patch that measures personal UV doses. The patch contains functional layers of ultrathin stretchable electronics and a photosensitive patterned dye that reacts to UV radiation. Color changes in the photosensitive dyes correspond to UV radiation intensity and are analyzed with a smartphone camera. A software application has feature recognition, lighting condition correction, and quantification algorithms that detect and quantify changes in color. These color changes are then correlated with corresponding shifts in UV dose, and compared to existing UV dose risk levels. The soft mechanics of the UV patch allow for multi-day wear in the presence of sunscreen and water. Two evaluation studies serve to demonstrate the utility of the UV patch during daily activities with and without sunscreen application.

A thin, skin-like, butterfly-shaped system combines colorimetry and wireless communication to capture precise dosimetry data in the UV-A and UV-B regions, and for determination of instantaneous UV exposure levels and skin temperature via a smartphone interface is described by J. A. Rogers and co-workers on page 1604465. Quantitative information follows from automated L*a*b* color space analysis of digital images of the devices.

The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1) was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.

Precise, quantitative in vivo monitoring of hydration levels in the near surface regions of the skin can be useful in preventing skin-based pathologies, and regulating external appearance. Here we introduce multimodal sensors with important capabilities in this context, rendered in soft, ultrathin, ‘skin-like’ formats with numerous advantages over alternative technologies, including the ability to establish intimate, conformal contact without applied pressure, and to provide spatiotemporally resolved data on both electrical and thermal transport properties from sensitive regions of the skin. Systematic in vitro studies and computational models establish the underlying measurement principles and associated approaches for determination of temperature, thermal conductivity, thermal diffusivity, volumetric heat capacity, and electrical impedance using simple analysis algorithms. Clinical studies on 20 patients subjected to a variety of external stimuli validate the device operation and allow quantitative comparisons of measurement capabilities to those of existing state-of-the-art tools.

Ultraviolet (UV) solar radiation is a leading cause of skin disease. Quantitative, continuous knowledge of exposure levels can enhance awareness and lead to improved health outcomes. Devices that offer this type of measurement capability in formats that can seamlessly integrate with the skin are therefore of interest. This paper introduces materials, device designs, and data acquisition methods for a skin‐like, or “epidermal,” system that combines colorimetric and electronic function for precise dosimetry in the UV‐A and UV‐B regions of the spectrum, and for determination of instantaneous UV exposure levels and skin temperature. The colorimetric chemistry uses (4‐phenoxyphenyl)diphenylsulfonium triflate (PPDPS‐TF) with crystal violet lactone (CVL) and Congo red for UV‐A and UV‐B operation, respectively, when integrated with suitable optical filters. Coatings of poly(ethylene‐vinylacetate) (PEVA) protect the functional materials from sunscreen and other contamination. Quantitative information follows from automated L*a*b* color space analysis of digital images of the devices to provide accurate measurements when calibrated against standard nonwearable sensors. Techniques of screen printing and lamination allow aesthetic designs and integration with epidermal near field communication platforms, respectively. The result is a set of attractive technologies for managing UV exposure at a personal level and on targeted regions of the body.

Quantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor micro-environment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines (19)F magnetic resonance imaging ((19)F-MRI) R 1 mapping with diffusion-based multispectral (MS) analysis is introduced. This approach restricts the partial pressure of oxygen (pO2) measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS (19)F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1) and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980). GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment.

Fig.2. (A) Mean ΔpO2 (day 3-day 0) in four tissue classes. (B) Mean ΔpO2 change in viable tumor (with std error). * p<0.05 vs control. # p<0.05, ## p<0.01 vs pre-tx. Dual PI3K/mTOR Inhibition Suppresses Tumor pO2 within Viable Tumor Assessed by F-MRI and Multispectral Analysis Yunzhou Shi, Jason Oeh, Jeffrey Eastham-Anderson, Sharon Yee, David Finkle, Franklin V. Peale, Jed Ross, Maj Hedehus, Nicholas van Bruggen, Rayna Venook, Sarajane Ross, Deepak Sampath, and Richard A. D. Carano Biomedical Imaging, Genentech Inc.(Roche Group), South San Francisco, CA, United States, Translational Oncology, Genentech Inc.(Roche Group), South San Francisco, CA, United States, Pathology, Genentech Inc.(Roche Group), South San Francisco, CA, United States

In vivo imaging of white matter is important for the mechanistic understanding of demyelination and evaluation of remyelination therapies. Although white matter can be visualized by a strong coherent anti-Stokes Raman scattering (CARS) signal from axonal myelin, in vivo repetitive CARS imaging of the spinal cord remains a challenge due to complexities induced by the laminectomy surgery. We present a careful experimental design that enabled longitudinal CARS imaging of de- and remyelination at single axon level in live rats. In vivo CARS imaging of secretory phospholipase A2 induced myelin vesiculation, macrophage uptake of myelin debris, and spontaneous remyelination by Schwann cells are sequentially monitored over a 3 week period. Longitudinal visualization of de- and remyelination at a single axon level provides a novel platform for rational design of therapies aimed at promoting myelin plasticity and repair.

High-frequency electrical stimulation is becoming a promising therapy for neurological disorders, however the response of the central nervous system to stimulation remains poorly understood. The current work investigates the response of myelin to electrical stimulation by laser-scanning coherent anti-Stokes Raman scattering (CARS) imaging of myelin in live spinal tissues in real time. Paranodal myelin retraction at the nodes of Ranvier was observed during 200 Hz electrical stimulation. Retraction was seen to begin minutes after the onset of stimulation and continue for up to 10 min after stimulation was ceased, but was found to reverse after a 2 h recovery period. The myelin retraction resulted in exposure of Kv 1.2 potassium channels visualized by immunofluorescence. Accordingly, treating the stimulated tissue with a potassium channel blocker, 4-aminopyridine, led to the appearance of a shoulder peak in the compound action potential curve. Label-free CARS imaging of myelin coupled with multiphoton fluorescence imaging of immuno-labeled proteins at the nodes of Ranvier revealed that high-frequency stimulation induced paranodal myelin retraction via pathologic calcium influx into axons, calpain activation, and cytoskeleton degradation through spectrin break-down.

Myelin damage can lead to the loss of axonal conduction and paralysis in multiple sclerosis and spinal cord injury. Here, we show that acrolein, a lipid peroxidation product, can cause significant myelin damage in isolated guinea pig spinal cord segments. Acrolein-mediated myelin damage is particularly conspicuous in the paranodal region in both a calcium dependent (nodal lengthening) and a calcium-independent manner (paranodal myelin splitting). In addition, paranodal protein complexes can dissociate with acrolein incubation. Degraded myelin basic protein is also detected at the paranodal region. Acrolein-induced exposure and redistribution of paranodal potassium channels and the resulting axonal conduction failure can be partially reversed by 4-AP, a potassium channel blocker. From this data, it is clear that acrolein is capable of inflicting myelin damage as well as axonal degeneration, and may represent an important factor in the pathogenesis in multiple sclerosis and spinal cord injury.

** ** NS Mapping in vivo Tumor Oxygenation within Viable Tumor using F MRI and Multispectral Analysis Yunzhou Shi, David Finkle, Franklin Peale, Jed Ross, Maj Hedehus, Nicholas Van Bruggen, Suzanna Clark, Rayna Venook, Sarajane Ross, and Richard Carano Biomedical Imaging, Genentech Inc.(Roche group), South San Francisco, CA, United States, Translational Oncology, Genentech Inc.(Roche group), South San Francisco, CA, United States, Pathology, Genentech Inc.(Roche group), South San Francisco, CA, United States

The choroid plexus (CP), constituting the blood–cerebrospinal fluid barrier, has the capacity to remove beta-amyloid (Aβ) from the cerebrospinal fluid. Our previous work indicates that exposure to lead (Pb) results in Aβ accumulation in the CP by decreasing the expression of low density lipoprotein receptor protein-1 (LRP1), a protein involved in the transport and clearance of Aβ. The current study was designed to explore the relationship between Aβ accumulation, protein kinase C (PKC) activity, and LRP1 status in the CP following Pb exposure. Confocal microscopy revealed that LRP1 was primarily localized in the cytosol of the CP in control rats and migrated distinctly towards the apical surface and the microvilli following acute Pb exposure (27mg Pb/kg, i.p., 24h). Co-immunostaining revealed a co-localization of both PKC-δ and LRP1 in the cytosol of control rats, with a distinct relocalization of both towards the apical membrane following Pb exposure. Preincubation of the tissues with PKC-δ inhibitor rottlerin (2μM) prior to Pb exposure in vitro, resulted in abolishing the Pb-induced relocalization of LRP1 to the apical surface. Importantly, a significant elevation in intracellular Aβ levels (p<0.01) was observed in the cytosol of the CP following Pb exposure, which was abolished following preincubation with rottlerin. In addition, rottlerin caused a relocalization of Aβ from the cytosol to the nucleus in both Pb-treated and control CP tissues. Finally, co-immunoprecipitation studies revealed a strong protein-protein interaction between LRP1 and PKC-δ in the CP. These studies suggest that Pb exposure disrupts Aβ homeostasis at the CP, owing partly to a Pb-induced relocalization of LRP1 via PKC-δ.

Desorption electrospray ionization (DESI) mass spectrometry (MS) is used in an imaging mode to interrogate the lipid profiles of 15 μm thin tissue cross sections of injured rat spinal cord and normal healthy tissue. Increased relative intensities of fatty acids, diacylglycerols, and lysolipids (between +120% and +240%) as well as a small decrease in intensities of lipids (-30%) were visualized in the lesion epicenter and adjacent areas after spinal cord injury. This indicates the hydrolysis of lipids during the demyelination process due to activation of phospholipase A(2) enzyme. In addition, signals corresponding to oxidative degradation products, such as prostaglandin and hydroxyeicosatetraenoic acid, exhibited increased signal intensity by a factor of 2 in the negative ion mode in lesions relative to the normal healthy tissue. Analysis of malondialdehyde, a product of lipid peroxidation and marker of oxidative stress, was accomplished in the ambient environment using reactive DESI mass spectrometry imaging. This was achieved by electrospraying reagent solution containing dinitrophenylhydrazine as high-velocity charged droplets onto the tissue section. The hydrazine reacts selectively and rapidly with the carbonyl groups of malondialdehyde, and signal intensity of twice the intensity was detected in the lesions compared to healthy spinal cord. With a small amount of tissue sample, DESI-MS imaging provides information on the composition and distribution of specific compounds (limited by the occurrence of isomeric lipids with very similar fragmentation patterns) in lesions after spinal cord injury in comparison with normal healthy tissue allowing identification of the extent of the lesion and its repair.

Importance of the field: Spontaneously constructed from block copolymers in aqueous media, the polymer micelle has been extensively studied as a potential carrier of poorly water-soluble drugs, but cellular uptake pathways and stability of micelles in blood have not yet been clearly understood. An in-depth insight into the physical and biological behaviors of polymer micelles is necessitated for designing next-generation micelles.Areas covered in this review: This review suggests possible solutions to improve micellar drug loading capacity, scrutinizes the parameters influencing the micelle stability in blood, and also discusses the fate of micelles in cellular and in vivo environment, respectively. Direct and indirect evidences from the literatures mostly published after 90's were collected, analyzed and summarized.What the reader will gain: A critical analysis of micelle's stability in vivo and micelle-cell interaction is provided to highlight the key issues to be addressed to affirm that micelle can properly work as a drug carrier in clinical settings.Take home message: With a clear understanding of its behaviors in biological environment, the polymer micelle is a promising nanocarrier for chemotherapy.

Imaging mass spectrometry allows for the direct investigation of tissue samples to identify specific biological compounds and determine their spatial distributions. Desorption electrospray ionization (DESI) mass spectrometry has been used for the imaging and analysis of rat spinal cord cross sections. Glycerophospholipids and sphingolipids, as well as fatty acids, were detected in both the negative and positive ion modes and identified through tandem mass spectrometry (MS/MS) product ion scans using collision-induced dissociation and accurate mass measurements. Differences in the relative abundances of lipids and free fatty acids were present between white and gray matter areas in both the negative and positive ion modes. DESI-MS images of the corresponding ions allow the determination of their spatial distributions within a cross section of the rat spinal cord, by scanning the DESI probe across the entire sample surface. Glycerophospholipids and sphingolipids were mostly detected in the white matter, while the free fatty acids were present in the gray matter. These results show parallels with reported distributions of lipids in studies of rat brain. This suggests that the spatial intensity distribution reflects relative concentration differences of the lipid and fatty acid compounds in the spinal cord tissue. The "butterfly" shape of the gray matter in the spinal cord cross section was resolved in the corresponding ion images, indicating that a lateral resolution of better than 200 μm was achieved. The selected ion images of lipids are directly correlated with anatomic features on the spinal cord corresponding to the white and the gray matter.