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Flexible and stretchable electronic systems for epidermal electronics
Provided herein are skin-mounted biomedical devices and methods of making and using biomedical devices for sensing and actuation applications. For example, flexible and/or stretchable biomedical devices are provided, including electronic devices useful for establishing conformal contact with the skin of a subject. Devices disclosed herein can comprise a plurality of sensing and/or actuating devices provided as part of a skin-mounted flexible or stretchable electronic circuit.
Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro
Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis–Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte K{sub m} and V{sub max} values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and C{sub max} was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers. - Highlights: • An entirely in silico/in vitro approach to predict in vivo exposure to dermally applied hair dyes • Skin penetration and epidermal conversion assessed in human skin explants and HaCaT • Systemic metabolism was modeled using hepatocyte cultures. • Toxicokinetically relevant parameters were applied to estimate systemic exposure. • There was a good agreement between in vitro and in vivo data.
Soft Core/Shell Packages for Stretchable Electronics
This paper presents materials and core/shell architectures that provide optimized mechanical properties in packages for stretchable electronic systems. Detailed experimental and theoretical studies quantitatively connect the geometries and elastic properties of the constituent materials to the overall mechanical responses of the integrated systems, with a focus on interfacial stresses, effective modulus, and maximum extent of elongation. Specific results include core/shell designs that lead to peak values of the shear and normal stresses on the skin that remain less than 10 kPa even for applied strains of up to 20%, thereby inducing minimal somatosensory perception of the device on the human skin. Additional, strain-limiting mesh structures embedded in the shell improve mechanical robustness by protecting the active components from strains that would otherwise exceed the fracture point. Demonstrations in precommercial stretchable electronic systems illustrate the utility of these concepts.
Patient Selection for Clinical Trials Eliminating Surgery for HER2-Positive Breast Cancer Treated with Neoadjuvant Systemic Therapy
Background: Patients with epidermal growth factor receptor 2-positive (HER2+) breast cancer and pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) may be candidates for nonoperative clinical trials if residual invasive and in situ disease are eradicated. Methods: This study analyzed 280 patients with clinical T1-2N0-1 HER2+ breast cancer who underwent NST followed by surgical resection to determine key characteristics of patients with pCR in the breast and lymph nodes compared with those with residual disease. Results: Of the 280 patients, 102 (36.4%) had pCR in the breast and lymph nodes after NST, and 50 patients (17.9%) had residual ductal carcinoma in situ (DCIS) in the breast only. For 129 patients (46.1%), DCIS was present on the pretreatment biopsy, and NST failed to eradicate the DCIS component in 64.3%. Patients with residual disease were more likely to have hormone receptor-positive (HR+) tumors than those with negative tumors (73.4% vs. 50.8%; p < 0.0001). Radiologic response (odds ratio [OR], 5.62; p = 0.002) and HR+ status (OR, 2.56; p < 0.0001) were predictive of residual disease. Combined imaging methods after NST had a sensitivity of 97.1% and a negative predictive value of 70.6% for detection of residual disease. Patients with invasive disease and DCIS shown on the pretreatment core biopsy were less likely than those without DCIS to achieve pCR in the breast (31% vs. 43%; p = 0.038). Conclusion: The study results delineate and identify unique characteristics associated with HER2+ breast cancers that are important in selecting patients for inclusion in clinical trials assessing nonoperative management after NST, and the low negative predictive value of imaging mandates image-guided biopsy for selection.
Model system for plant cell biology: GFP imaging in living onion epidermal cells
The ability to visualize organelle localization and dynamics is very useful in studying cellular physiological events. Until recently, this has been accomplished using a variety of staining methods. However, staining can give inaccurate information due to nonspecific staining, diffusion of the stain or through toxic effects. The ability to target green fluorescent protein (GFP) to various organelles allows for specific labeling of organelles in vivo. The disadvantages of GFP thus far have been the time and money involved in developing stable transformants or maintaining cell cultures for transient expression. In this paper, we present a rapid transient expression system using onion epidermal peels. We have localized GFP to various cellular compartments (including the cell wall) to illustrate the utility of this method and to visualize dynamics of these compartments. The onion epidermis has large, living, transparent cells in a monolayer, making them ideal for visualizing GFP. This method is easy and inexpensive, and it allows for testing of new GFP fusion proteins in a living tissue to determine deleterious effects and the ability to express before stable transformants are attempted.
Mechanotransduction and the Cytoskeleton
Two intellectual developments in the lab suggested a more powerful approach to the problem defined in the original statement. These were discussed with the "Program Chief', who agreed that an alteration of approach was desirable. Second expansion of our work was on the computational optical sectioning microscope (COSM). Additionally, we hoped to visualize the channels with respect to cytoskeletal entities. We have identified major here-to-fore unknown cytoskeletal structure in our representative experimental system, the onion epidermal cell, and have named this structure the endomembrane grant.
Local Thermal Ablation with Continuous EGFR Tyrosine Kinase Inhibitors for EGFR-Mutant Non-small Cell Lung Cancers that Developed Extra-Central Nervous System (CNS) Oligoprogressive Disease
Background: Most epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs) experience oligoprogressive disease. Local ablation for isolated resistant sites continued with the original EGFR-TKI showed good efficacy in these patients. We conducted this multicenter retrospective study to investigate the potential benefit of thermal ablation in NSCLC patients that developed extra-central nervous system (CNS) oligoprogressive disease during TKI treatment. Methods: A total of 71 EGFR-mutant patients treated with EGFR-TKIs were identified. Progression-free survival 1 (PFS1) was calculated from the initiation of TKI treatment to first progression. Patients with metastatic sites ≤ 3 in less than 3 extra-CNS organs suitable for local ablation therapy received either radiofrequency ablation or microwave ablation to these sites and continued on the original TKIs. PFS2 was defined from the first progression to second progression after ablation. Results: The median PFS1 for all patients was 11.8 months. Eighty extra-CNS oligoprogressive lesions in 71 patients were ablated. Thirty-six of 71 patients progressed after thermal ablation and 31 of whom died during the study period. The median PFS2 after thermal ablation was 10.0 months, and the median overall survival was 26.4 months. PFS1 and PFS2 were highly correlated with OS, whereas PFS1 was not correlated with PFS2. The numbers of oligoprogressive lesions were significantly and independently associated with PFS2. Conclusion: Local thermal ablation for the oligoprogressive lesions with continuous EGFR-TKI treatment is associated with additional 10 months of disease control and should be recommended in TKI acquired resistant-NSCLC patients.
Laser System for Biological Tissues Final Report CRADA No. TSB-1549-98
The goal of this project was to demonstrate a laser-based system which can shape and resurface the epidermal plate as well as generate images on acrylic. The prototype system used a pulsed diode pumped laser to ablate and shape the surface using a high absorption pigment. A CCD camera will image the epidermal plate and computer software will analyze the image to guide laser ablation. . The deliverable was for LLNL to generate a final report upon completion of the project, which summarized the results of the project and the schematics for the prototype device. This project consisted of six (6) main tasks, all of which would be performed at LLNL over a seven (7) month period. Due to lack of manpower availability which caused delays in the project work, and minor redesigns which delayed manufacturing, the project was extended for an additional five months.
Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 2: Technical analysis
A technical analysis on the feasibility of commercial manufacturing of pharmaceuticals in space is presented. The method of obtaining pharmaceutical company involvement, laboratory results of the separation of serum proteins by the continuous flow electrophoresis process, the selection and study of candidate products, and their production requirements is described. The candidate products are antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin and interferon. Production mass balances for antihemophelic factor, beta cells, and erythropoietin were compared for space versus ground operation. A conceptual description of a multiproduct processing system for space operation is discussed. Production requirements for epidermal growth factor of alpha-1-antitrypsin and interferon are presented.
Protein expression and gene editing in monocots using foxtail mosaic virus vectors
Abstract Plant viruses can be engineered to carry sequences that direct silencing of target host genes, expression of heterologous proteins, or editing of host genes. A set of foxtail mosaic virus (FoMV) vectors was developed that can be used for transient gene expression and single guide RNA delivery for Cas9‐mediated gene editing in maize, Setaria viridis , and Nicotiana benthamiana . This was accomplished by duplicating the FoMV capsid protein subgenomic promoter, abolishing the unnecessary open reading frame 5A, and inserting a cloning site containing unique restriction endonuclease cleavage sites immediately after the duplicated promoter. The modified FoMV vectors transiently expressed green fluorescent protein (GFP) and bialaphos resistance (BAR) protein in leaves of systemically infected maize seedlings. GFP was detected in epidermal and mesophyll cells by epifluorescence microscopy, and expression was confirmed by Western blot analyses. Plants infected with FoMV carrying the bar gene were temporarily protected from a glufosinate herbicide, and expression was confirmed using a rapid antibody‐based BAR strip test. Expression of these proteins was stabilized by nucleotide substitutions in the sequence of the duplicated promoter region. Single guide RNAs expressed from the duplicated promoter mediated edits in the N. benthamiana Phytoene desaturase gene, the S. viridis Carbonic anhydrase 2 gene, and the maize HKT1 gene encoding a potassium transporter. The efficiency of editing was enhanced in the presence of synergistic viruses and a viral silencing suppressor. This work expands the utility of FoMV for virus‐induced gene silencing (VIGS), virus‐mediated overexpression (VOX), and virus‐enabled gene editing (VEdGE) in monocots.
ALD1 accumulation in Arabidopsis epidermal plastids confers local and non-autonomous disease resistance
The Arabidopsis plastid-localized ALD1 protein acts in the lysine catabolic pathway that produces infection-induced pipecolic acid (Pip), Pip derivatives, and basal non-Pip metabolite(s). ALD1 is indispensable for disease resistance associated with Pseudomonas syringae infections of naïve plants as well as those previously immunized by a local infection, a phenomenon called systemic acquired resistance (SAR). Pseudomonas syringae is known to associate with mesophyll as well as epidermal cells. To probe the importance of epidermal cells in conferring bacterial disease resistance, we studied plants in which ALD1 was only detectable in the epidermal cells of specific leaves. Local disease resistance and many features of SAR were restored when ALD1 preferentially accumulated in the epidermal plastids at immunization sites. Interestingly, SAR restoration occurred without appreciable accumulation of Pip or known Pip derivatives in secondary distal leaves. Our findings establish that ALD1 has a non-autonomous effect on pathogen growth and defense activation. We propose that ALD1 is sufficient in the epidermis of the immunized leaves to activate SAR, but basal ALD1 and possibly a non-Pip metabolite(s) are also needed at all infection sites to fully suppress bacterial growth. Thus, epidermal plastids that contain ALD1 play a key role in local and whole-plant immune signaling.
Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation
For a better assessment of radiation risk in space, an understanding of the responses of human cells, especially the epithelial cells, to low- and high-LET radiation is essential. In our laboratory, we have successfully developed techniques to study the neoplastic transformation of two human epithelial cell systems by ionizing radiation. These cell systems are human mammary epithelial cells (H184B5) and human epidermal keratinocytes (HEK). Both cell lines are immortal, anchorage dependent for growth, and nontumorigenic in athymic nude mice. Neoplastic transformation was achieved by irradiating cells successively. Our results showed that radiogenic cell transformation is a multistep process and that a single exposure of ionizing radiation can cause only one step of transformation. It requires, therefore, multihits to make human epithelial cells fully tumorigenic. Using a simple karyotyping method, we did chromosome analysis with cells cloned at various stages of transformation. We found no consistent large terminal deletion of chromosomes in radiation-induced transformants. Some changes of total number of chromosomes, however, were observed in the transformed cells. These transformants provide an unique opportunity for further genetic studies at a molecular level.
Spatial organization of cellulose microfibrils and matrix polysaccharides in primary plant cell walls as imaged by multichannel atomic force microscopy
Summary We used atomic force microscopy ( AFM ), complemented with electron microscopy, to characterize the nanoscale and mesoscale structure of the outer (periclinal) cell wall of onion scale epidermis – a model system for relating wall structure to cell wall mechanics. The epidermal wall contains ~100 lamellae, each ~40 nm thick, containing 3.5‐nm wide cellulose microfibrils oriented in a common direction within a lamella but varying by ~30 to 90° between adjacent lamellae. The wall thus has a crossed polylamellate, not helicoidal, wall structure. Montages of high‐resolution AFM images of the newly deposited wall surface showed that single microfibrils merge into and out of short regions of microfibril bundles, thereby forming a reticulated network. Microfibril direction within a lamella did not change gradually or abruptly across the whole face of the cell, indicating continuity of the lamella across the outer wall. A layer of pectin at the wall surface obscured the underlying cellulose microfibrils when imaged by FESEM , but not by AFM . The AFM thus preferentially detects cellulose microfibrils by probing through the soft matrix in these hydrated walls. AFM ‐based nanomechanical maps revealed significant heterogeneity in cell wall stiffness and adhesiveness at the nm scale. By color coding and merging these maps, the spatial distribution of soft and rigid matrix polymers could be visualized in the context of the stiffer microfibrils. Without chemical extraction and dehydration, our results provide multiscale structural details of the primary cell wall in its near‐native state, with implications for microfibrils motions in different lamellae during uniaxial and biaxial extensions.
Cancer stem cell-like population is preferentially suppressed by EGFR-TKIs in EGFR-mutated PC-9 tumor models
Highlights: • EGFR-TKIs strongly inhibited the β-catenin signal and decreased CSCs sorted out by SP cells. • The reduction of CSCs significantly reduced the migration capability. • Targeting β-catenin could be a potential strategy for EGFR-mutated NSCLC. Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal.
Optical Microscopy-Guided Laser Ablation Electrospray Ionization Ion Mobility Mass Spectrometry: Ambient Single Cell Metabolomics with Increased Confidence in Molecular Identification
Single cell analysis is a field of increasing interest as new tools are continually being developed to understand intercellular differences within large cell populations. Laser-ablation electrospray ionization mass spectrometry (LAESI-MS) is an emerging technique for single cell metabolomics. Over the years, it has been validated that this ionization technique is advantageous for probing the molecular content of individual cells in situ. Here, we report the integration of a microscope into the optical train of the LAESI source to allow for visually informed ambient in situ single cell analysis. Additionally, we have coupled this ‘LAESI microscope’ to a drift-tube ion mobility mass spectrometer to enable separation of isobaric species and allow for the determination of ion collision cross sections in conjunction with accurate mass measurements. This combined information helps provide higher confidence for structural assignment of molecules ablated from single cells. Here, we show that this system enables the analysis of the metabolite content of Allium cepa epidermal cells with high confidence structural identification together with their spatial locations within a tissue.
Covisualization in living onion cells of putative integrin, putative spectrin, actin, putative intermediate filaments, and other proteins at the cell membrane and in an endomembrane sheath
Covisualizations with wide-field computational optical-sectioning microscopy of living epidermal cells of the onion bulb scale have evidenced two major new cellular features. First, a sheath of cytoskeletal elements clads the endomembrane system. Similar elements clad the inner faces of punctate plasmalemmal sites interpreted as plasmalemmal control centers. One component of the endomembrane sheath and plasmalemmal control center cladding is anti-genicity-recognized by two injected antibodies against animal spectrin. Immunoblots of separated epidermal protein also showed bands recognized by these antibodies. Injected phalloidin identified F-actin with the same cellular distribution pattern, as did antibodies against intermediate-filament protein and other cytoskeletal elements known from animal cells. Injection of general protein stains demonstrated the abundance of endomembrane sheath protein. Second, the endomembrane system, like the plasmalemmal puncta, contains antigen recognized by an anti-beta 1 integrin injected into the cytoplasm. Previously, immunoblots of separated epidermal protein were shown to have a major band recognized both by this antibody prepared against a peptide representing the cytosolic region of beta 1 integrin and an antibody against the matrix region of beta 1 integrin. The latter antiboby also identified puncta at the external face of protoplasts. It is proposed that integrin and associated transmembrane proteins secure the endomembrane sheath and transmit signals between it and the lumen or matrix of the endoplasmic reticulum and organellar matrices. This function is comparable to that proposed for such transmembrane linkers in the plasmalemmal control centers, which also appear to bind cytoskeleton and a host of related molecules and transmit signals between them and the wall matrix. It is at the plasmalemmal control centers that the endoplasmic reticulum, a major component of the endomembrane system, attaches to the plasma membrane.
Elastomeric Sensing of Pressure with Liquid Metal and Wireless Inductive Coupling
This project describes resistance-based soft sensors filled with liquid metal, which permit measurements of large strains (0 percent to 110 percent), associated with small forces of less than 30 Newtons. This work also demonstrates a methodology for wireless transfer of these strain measurements without connected electrodes. These sensors allow intermittent detection of pressure on soft membranes with low force. Adapting these sensors for passive wireless pressure sensing will eliminate the need for embedded batteries, and will allow the sensors to transmit pressure data through non-conductive materials including glass and acrylic. The absence of batteries allows us to embed these sensors into materials for long-term use because the sensors only use passive analog circuit elements. We found the oxidation of the liquid metal (eutectic gallium indium) plays a role in the repeatability of the soft sensors. We investigated how the oxidation layer affected the behavior of the sensor by encapsulating materials (silicone, fluorosilicone, and PVC) with varied permeabilities to oxygen. We measured the effects of mechanical loading on the oxidation layer and the effects of wireless inductive coupling on the oxidation layer. We concluded our research by investigating the effects of embedding self-resonant circuits into polydimethylsiloxane (PDMS). Efforts to design engineered systems with soft materials are a growing field with progress in soft robotics, epidermal electronics, and wearable electronics. In the field of soft robotics, PDMS-based grippers are capable of picking up delicate objects because their form-fitting properties allow them to conform to the shape of objects more easily than conventional robotic grippers. Epidermal devices also use PDMS as a substrate to hold electronic components such as radios, sensors, and power supply circuits. Additionally, PDMS-based soft sensors can monitor human motion with liquid metal embedded within micro-channels. Passive wireless sensors have applications in structural health monitoring and medical health monitoring. Doctors can take wireless blood pressure measurements inside arteries to monitor the progression of heart disease. Glaucoma patients can use this technology to monitor the pressure in their eyes to track the progression of the disease.