Fibrin is an attractive material for regenerative medicine applications. It not only forms a polymer but also contains cryptic matrikines that are released upon its activation/degradation and enhance the regenerative process. Despite this advantageous biology associated with fibrin, commercially available systems (e.g. TISSEEL) display limited regenerative capacity. This limitation is in part due to formulations that are optimized for tissue sealant applications and result in dense fibrous networks that limit cell infiltration. Recent evidence suggests that polymerization knob 'B' engagement of polymerization hole 'b' activates an alternative polymerization mechanism in fibrin, which may result in altered single fiber mechanical properties. We hypothesized that augmenting fibrin polymerization through the addition of PEGylated knob peptides with specificity to hole 'b' (AHRPYAAC-PEG) would result in distinct fibrin polymer architectures with grossly different physical properties. Polymerization dynamics, polymer architecture, diffusivity, viscoelasticity, and degradation dynamics were analyzed. Results indicate that specific engagement of hole 'b' with PEGylated knob 'B' conjugates during polymerization significantly enhances the porosity of and subsequent diffusivity through fibrin polymers. Paradoxically, these polymers also display increased viscoelastic properties and decreased susceptibility to degradation. As a result, fibrin polymer strength was significantly augmented without any adverse effects on angiogenesis within the modified polymers.
Pathology is a medical subspecialty that practices the diagnosis of disease. Microscopic examination of tissue reveals information enabling the pathologist to render accurate diagnoses and to guide therapy. The basic process by which anatomic pathologists render diagnoses has remained relatively unchanged over the last century, yet advances in information technology now offer significant opportunities in image-based diagnostic and research applications. Pathology has lagged behind other healthcare practices such as radiology where digital adoption is widespread. As devices that generate whole slide images become more practical and affordable, practices will increasingly adopt this technology and eventually produce an explosion of data that will quickly eclipse the already vast quantities of radiology imaging data. These advances are accompanied by significant challenges for data management and storage, but they also introduce new opportunities to improve patient care by streamlining and standardizing diagnostic approaches and uncovering disease mechanisms. Computer-based image analysis is already available in commercial diagnostic systems, but further advances in image analysis algorithms are warranted in order to fully realize the benefits of digital pathology in medical discovery and patient care. In coming decades, pathology image analysis will extend beyond the streamlining of diagnostic workflows and minimizing interobserver variability and will begin to provide diagnostic assistance, identify therapeutic targets, and predict patient outcomes and therapeutic responses.
Engineering and functionalizing magnetic nanoparticles have been an area of the extensive research and development in the biomedical and nanomedicine fields. Because their biocompatibility and toxicity are well investigated and better understood, magnetic nanoparticles, especially iron oxide nanoparticles, are better suited materials as contrast agents for magnetic resonance imaging (MRI) and for image-directed delivery of therapeutics. Given tunable magnetic properties and various surface chemistries from the coating materials, most applications of engineered magnetic nanoparticles take advantages of their superb MRI contrast enhancing capability as well as surface functionalities. It has been found that MRI contrast enhancement by magnetic nanoparticles is highly dependent on the composition, size and surface properties as well as the degree of aggregation of the nanoparticles. Therefore, understanding the relationships between these intrinsic parameters and the relaxivities that contribute to MRI contrast can lead to establishing essential guidance that may direct the design of engineered magnetic nanoparticles for theranostics applications. On the other hand, new contrast mechanism and imaging strategy can be developed based on the novel properties of engineered magnetic nanoparticles. This review will focus on discussing the recent findings on some chemical and physical properties of engineered magnetic nanoparticles affecting the relaxivities as well as the impact on MRI contrast. Furthermore, MRI methods for imaging magnetic nanoparticles including several newly developed MRI approaches aiming at improving the detection and quantification of the engineered magnetic nanoparticles are described.
A microneedle patch coated with vaccine simplifies vaccination by using a patch-based delivery method and targets vaccination to the skin for superior immunogenicity compared to intramuscular injection. Previous studies of microneedles have demonstrated effective vaccination using freshly prepared microneedles, but the issue of long-term vaccine stability has received only limited attention. Here, we studied the long-term stability of microneedles coated with whole inactivated influenza vaccine guided by the hypothesis that crystallization and phase separation of the microneedle coating matrix damages influenza vaccine coated onto microneedles. In vitro studies showed that the vaccine lost stability as measured by hemagglutination activity in proportion to the degree of coating matrix crystallization and phase separation. Transmission electron microscopy similarly showed damaged morphology of the inactivated virus vaccine associated with crystallization. In vivo assessment of immune response and protective efficacy in mice further showed reduced vaccine immunogenicity after influenza vaccination using microneedles with crystallized or phase-separated coatings. This work shows that crystallization and phase separation of the dried coating matrix are important factors affecting long-term stability of influenza vaccine-coated microneedles.
Objective: To show the responsiveness of tissue-engineered human endometrial stroma to combinations of hormones that mimic the secretory and menstrual phases of the cycle. Design: In vitro experimental study. Setting: University uterine biology research laboratory. Patient(s): None. Intervention(s): Telomerase immortalized human endometrial stromal cells cultured in monolayers (two-dimensional, 2D) or encapsulated in a collagen I hydrogel (three-dimensional, 3D) to create a simplified tissue-engineered stroma were exposed to hormone treatments mimicking early and late secretory phases, decidualization, and steroid withdrawal conditions to recapitulate menstruation. Main Outcome Measure(s): Morphologic and biochemical markers of decidualization and collagenase activity. Result(s): The 3D tissue can manifest changes in morphology and biochemical markers of decidualization similar to 2D culture and characteristic of endometrial stroma in vivo. Unlike 2D culture, the 3D tissue responded to steroid withdrawal by increased collagenase activity and tissue breakdown. Conclusion(s): Three-dimensional tissue-engineered endometrial stroma can mimic secretory and menstrual phases of the cycle and may be useful for studying uterine receptivity and menstruation in a physiological endocrine environment.
Limited knowledge exists regarding the forces which act on devices implanted to the heart's mitral valve. Developing a transducer to measure the peak force magnitudes, time rates of change, and relationship with left ventricular pressure will aid in device development. A novel force transducer was developed and implanted in the mitral valve annulus of an ovine subject. In the post-cardioplegic heart, septal-lateral and transverse forces were continuously measured for cardiac cycles reaching a peak left ventricular pressure of 90. mmHg. Each force was seen to increase from ventricular diastole and found to peak at mid-systole. The mean change in septal-lateral and transverse forces throughout the cardiac cycle was 4.4±0.2. N and 1.9±0.1. N respectively. During isovolumetric contraction, the septal-lateral and transverse forces were found to increase at peak rate of 143±8. N/s and 34±9. N/s, respectively. Combined, this study provides the first quantitative assessment of septal-lateral and transverse forces within the contractile mitral annulus. The developed transducer was successful in measuring these forces whose methods may be extended to future studies. Upon additional investigation, these data may contribute to the safer development and evaluation of devices aimed to repair or replace mitral valve function.
Culturing multipotent adult mesenchymal stem cells as 3D aggregates augments their differentiation potential and paracrine activity. One caveat of stem cell spheroids, though, can be the limited diffusional transport barriers posed by the inherent 3D structure of the multicellular aggregates. In order to circumvent such limitations, polymeric microparticles have been incorporated into stem cell aggregates as a means to locally control the biochemical and physical properties of the 3D microenvironment. However, the introduction of biomaterials to the 3D stem cell microenvironment could alter the mechanical forces sensed by cells within aggregates, which in turn could impact various cell behaviors and overall spheroid mechanics. Therefore, the objective of this study was to determine the acute effects of biomaterial incorporation within mesenchymal stem cell spheroids on aggregate structure and mechanical properties. The results of this study demonstrate that although gelatin microparticle incorporation results in similar multi-cellular organization within human mesenchymal stem cell spheroids, the introduction of gelatin materials significantly impacts spheroid mechanical properties. The marked differences in spheroid mechanics induced by microparticle incorporation may hold major implications for . in vitro directed differentiation strategies and offer a novel route to engineer the mechanical properties of tissue constructs . ex vivo.
Multipollutant indicators of mobile source impacts are developed from readily available CO, NOx, and elemental carbon (EC) data for use in air quality and epidemiologic analysis. Two types of outcome-based Integrated Mobile Source Indicators (IMSI) are assessed. The first is derived from analysis of emissions of EC, CO, and NOxsuch that pollutant concentrations are mixed and weighted based on emission ratios for both gasoline and diesel vehicles. The emission-based indicators (IMSIEB) capture the impact of mobile sources on air quality estimated from receptor models and their uncertainty is comparable to measurement and source apportionment uncertainties. The IMSIEBhave larger correlation between two different receptor sites impacted by traffic than single pollutants, suggesting they are better indicators of the local impact of mobile sources. A sensitivity analysis of fractions of pollutants in a two-pollutant mixture and the inclusion in an epidemiologic model is conducted to develop a second set of indicators based on health outcomes. The health-based indicators (IMSIHB) are weighted combinations of CO, NOx, and EC pairs that have the lowest P value in their association with cardiovascular disease emergency department visits, possibly due to their better spatial representativeness. These outcome-based, multipollutant indicators can provide support for the setting of multipollutant air quality standards and other air quality management activities. Implications: Integrated mobile source indicators (IMSI) were developed and assessed for use in air quality and epidemiologic analysis. IMSI contribute to fill the gap in the path towards a multipollutant air quality approach in two aspects: IMSI represent an innovative way to identify mixtures of pollutants based on outcomes and constitutes an alternative approach to assess multipollutant health effects. IMSI developed for mobile sources can be easily applied to other sources. Results can support the setting of multipollutant air quality standards. Supplemental Material: Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of the Air & Waste Management Association for materials showing the estimation of uncertainties using propagation of errors, comparison of source impacts from CMB and PMF and wind direction and speed for the Jefferson Street monitoring location in Atlanta.
by
Yonggang Zhang;
Jianjun Liu;
Shaohua Yao;
Fang Li;
Lin Xin;
Mowen Lai;
Valerie Bracchi-Ricard;
Hong Xu;
William Yen;
Wentong Meng;
Shu Liu;
Leiting Yang;
Shaffiat Karmally;
Jin Liu;
Hongyan Zhu;
Jennifer Gordon;
Kamel Khalili;
Shanthi Srinivasan;
John R. Bethea;
Xianming Mo;
Wenhui Hu
Inflammatory mediators, many of which activate the signaling of nuclear factor kappa B (NFκB), have received increasing attention in the field of neurogenesis. NFκB signaling regulates neurite outgrowth and neural plasticity as well as the proliferation/apoptosis and terminal differentiation of neural stem cells (NSCs). Early neurogenesis from NSCs produces identical progeny through symmetric division and committed daughter cells through asymmetric division. Here, we show that NFκB signaling is required for NSC initial differentiation. The canonical IKKβ/IκBα/ p65 pathway is activated during the initial stages of neural differentiation induced by treatment with TNFα or withdrawal of epidermal growth factor/basic fibroblast growth factor. NSC-specific inhibition of NFκB in transgenic mice causes an accumulation of Nestin+/Sox2+/glial fibrillary acidic protein+NSCs. Inhibition of NFκB signaling in vitro blocks differentiation and asymmetric division and maintains NSCs in an undifferentiated state. The induction of initial differentiation and asymmetry by NFκB signaling occurs through the inhibition of C/EBPβ expression. Our data reveal a novel function of NFκB signaling in early neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases.
Background: Since current general interest in anesthesia is unknown, we analyzed internet keyword searches to gauge general interest in anesthesia in comparison with surgery and pain. Methods: The trend of keyword searches from 2004 to 2010 related to anesthesia and anaesthesia was investigated using Google Insights for Search. The trend of number of peer reviewed articles on anesthesia cited on PubMed and Medline from 2004 to 2010 was investigated. The average cost on advertising on anesthesia, surgery and pain was estimated using Google AdWords. Searching results in other common search engines were also analyzed. Correlation between year and relative number of searches was determined with p< 0.05 considered statistically significant. Results: Searches for the keyword "anesthesia" or "anaesthesia" diminished since 2004 reflected by Google Insights for Search (p< 0.05). The search for "anesthesia side effects" is trending up over the same time period while the search for "anesthesia and safety" is trending down. The search phrase "before anesthesia" is searched more frequently than "preanesthesia" and the search for "before anesthesia" is trending up. Using "pain" as a keyword is steadily increasing over the years indicated. While different search engines may provide different total number of searching results (available posts), the ratios of searching results between some common keywords related to perioperative care are comparable, indicating similar trend. The peer reviewed manuscripts on "anesthesia" and the proportion of papers on "anesthesia and outcome" are trending up. Estimates for spending of advertising dollars are less for anesthesia-related terms when compared to that for pain or surgery due to relative smaller number of searching traffic. Conclusions: General interest in anesthesia (anaesthesia) as measured by internet searches appears to be decreasing. Pain, preanesthesia evaluation, anesthesia and outcome and side effects of anesthesia are the critical areas that anesthesiologists should focus on to address the increasing concerns.