Design and construction of three-dimensional physiologically-based vascular branching networks for respiratory assist devices.

Microfluidic lab-on-a-chip devices are changing the way that in vitro diagnostics and drug development are conducted, based on the increased precision, miniaturization and efficiency of these systems relative to prior methods. However, the full potential of microfluidics as a platform for therapeutic medical devices such as extracorporeal organ support has not been realized, in part due to limitations in the ability to scale current designs and fabrication techniques toward clinically relevant rates of blood flow. Here we report on a method for designing and fabricating microfluidic devices supporting blood flow rates per layer greater than 10 mL min-1 for respiratory support applications, leveraging advances in precision machining to generate fully three-dimensional physiologically-based branching microchannel networks. The ability of precision machining to create molds with rounded features and smoothly varying channel widths and depths distinguishes the geometry of the microchannel networks described here from all previous reports of microfluidic respiratory assist devices, regarding the ability to mimic vascular blood flow patterns. These devices have been assembled and tested in the laboratory using whole bovine or porcine blood, and in a porcine model to demonstrate efficient gas transfer, blood flow and pressure stability over periods of several hours. This new approach to fabricating and scaling microfluidic devices has the potential to address wide applications in critical care for end-stage organ failure and acute illnesses stemming from respiratory viral infections, traumatic injuries and sepsis.

A high gas transfer efficiency microfluidic oxygenator for extracorporeal respiratory assist applications in critical care medicine.

Advances in microfluidics technologies have spurred the development of a new generation of microfluidic respiratory assist devices, constructed using microfabrication techniques capable of producing microchannel dimensions similar to those found in human capillaries and gas transfer films in the same thickness range as the alveolar membrane. These devices have been tested in laboratory settings and in some cases in extracorporeal animal experiments, yet none have been advanced to human clinical studies. A major challenge in the development of microfluidic oxygenators is the difficulty in scaling the technology toward high blood flows necessary to support adult humans; such scaling efforts are often limited by the complexity of the fabrication process and the manner in which blood is distributed in a three-dimensional network of microchannels. Conceptually, a central advantage of microfluidic oxygenators over existing hollow-fiber membrane-based configurations is the potential for shallower channels and thinner gas transfer membranes, features that reduce oxygen diffusion distances, to result in a higher gas transfer efficiency defined as the ratio of the volume of oxygen transferred to the blood per unit time to the active surface area of the gas transfer membrane. If this ratio is not significantly higher than values reported for hollow fiber membrane oxygenators (HFMO), then the expected advantage of the microfluidic approach would not be realized in practice, potentially due to challenges encountered in blood distribution strategies when scaling microfluidic designs to higher flow rates. Here, we report on scaling of a microfluidic oxygenator design from 4 to 92 mL/min blood flow, within an order of magnitude of the flow rate required for neonatal applications. This scaled device is shown to have a gas transfer efficiency higher than any other reported system in the literature, including other microfluidic prototypes and commercial HFMO cartridges. While the high oxygen transfer efficiency is a promising advance toward clinical scaling of a microfluidic architecture, it is accompanied by an excessive blood pressure drop in the circuit, arising from a combination of shallow gas transfer channels and equally shallow distribution manifolds. Therefore, next-generation microfluidic oxygenators will require novel design and fabrication strategies to minimize pressure drops while maintaining very high oxygen transfer efficiencies.

Miniaturized optical frequency reference for next-generation portable optical clocks.

Optical frequency standards, or lasers stabilized to atomic or molecular transitions, are widely used in length metrology and laser ranging, provide a backbone for optical communications and lie at the heart of next-generation optical atomic clocks. Here we demonstrate a compact, low-power optical frequency reference based on the Doppler-free, two-photon transition in rubidium-87 at 778 nm implemented on a micro-optics breadboard. Our optical reference achieves a fractional frequency instability of 2.9×10-12/τ for averaging times τ less than 103 s, has a volume of ≈35 cm3 and operates on ≈450 mW of electrical power. The advanced optical integration presented here demonstrates a key step towards the development of compact optical clocks and the broad dissemination of SI-traceable wavelength references.

Surface-emitting electroholographic SAW modulator.

We report the design and operation of a surface-emitting surface acoustic wave (SAW) acousto-optical modulator which behaves as a cm-scale linear hologram in response to an applied electronic waveform. The modulator is formed by an optical waveguide, transducer, and out-coupling surface grating on a 1 mm-thick lithium niobate substrate. We demonstrate the ability to load and illuminate a 9-region linear hologram into the modulator's 8 mm-long interaction region using applied waveforms of 280-320 MHz. To the best of the authors' knowledge, this is the first demonstration of a monolithically-integrated, surface-emitting SAW modulator fabricated using lithographic techniques. Applications include practical implementations of a holographic display.

An adaptable soft-mold embossing process for fabricating optically-accessible, microfeature-based culture systems and application toward liver stage antimalarial compound testing.

Advanced cell culture methods for modeling organ-level structure have been demonstrated to replicate in vivo conditions more accurately than traditional in vitro cell culture. Given that the liver is particularly important to human health, several advanced culture methods have been developed to experiment with liver disease states, including infection with Plasmodium parasites, the causative agent of malaria. These models have demonstrated that intrahepatic parasites require functionally stable hepatocytes to thrive and robust characterization of the parasite populations' response to investigational therapies is dependent on high-content and high-resolution imaging (HC/RI). We previously reported abiotic confinement extends the functional longevity of primary hepatocytes in a microfluidic platform and set out to instill confinement in a microtiter plate platform while maintaining optical accessibility for HC/RI; with an end-goal of producing an improved P. vivax liver stage culture model. We developed a novel fabrication process in which a PDMS soft mold embosses hepatocyte-confining microfeatures into polystyrene, resulting in microfeature-based hepatocyte confinement (µHEP) slides and plates. Our process was optimized to form both microfeatures and culture wells in a single embossing step, resulting in a 100 µm-thick bottom ideal for HC/RI, and was found inexpensively amendable to microfeature design changes. Microfeatures improved intrahepatic parasite infection rates and µHEP systems were used to reconfirm the activity of reference antimalarials in phenotypic dose-response assays. RNAseq of hepatocytes in µHEP systems demonstrated microfeatures sustain hepatic differentiation and function, suggesting broader utility for preclinical hepatic assays; while our tailorable embossing process could be repurposed for developing additional organ models.

The Effect of Improving Cycleway Environment on the Recreational Benefits of Bicycle Tourism.

Bicycle tourism is one of the popular physical activities for sport tourists. Since the physical environment may affect bicycling behavior, it becomes an important determinant for cyclists to choose a cycleway. Exploratory factor analysis is performed to extract the perception of environmental quality of cyclists into five main factors, including safety, light facilities, lane design, landscape, and environment cleanliness. The contingent behavior method (CBM) is adopted to measure the quality improvement projects in different scenarios of light facility and landscape improvement. The results showed that the improvement projects increased the intended number of trips and the recreational benefits of cyclists.

A bilayer small diameter in vitro vascular model for evaluation of drug induced vascular injury.

In pre-clinical safety studies, drug-induced vascular injury (DIVI) is defined as an adverse response to a drug characterized by degenerative and hyperplastic changes of endothelial cells and vascular smooth muscle cells. Inflammation may also be seen, along with extravasation of red blood cells into the smooth muscle layer (i.e., hemorrhage). Drugs that cause DIVI are often discontinued from development after considerable cost has occurred. An in vitro vascular model has been developed using endothelial and smooth muscle cells in co-culture across a porous membrane mimicking the internal elastic lamina. Arterial flow rates of perfusion media within the endothelial chamber of the model induce physiologic endothelial cell alignment. Pilot testing with a drug known to cause DIVI induced extravasation of red blood cells into the smooth muscle layer in all devices with no extravasation seen in control devices. This engineered vascular model offers the potential to evaluate candidate drugs for DIVI early in the discovery process. The physiologic flow within the co-culture model also makes it candidate for a wide variety of vascular biology investigations.

Comparison of measured and self-reported anthropometric information among firefighters: implications and applications.

This study evaluated the accuracy of self-reported body weight and height compared to measured values among firefighters and identified factors associated with reporting error. A total of 863 male and 88 female firefighters in four US regions participated in the study. The results showed that both men and women underestimated their body weight ( - 0.4 ± 4.1, - 1.1 ± 3.6 kg) and overestimated their height (29 ± 18 , 17 ± 16 mm). Women underestimated more than men on weight (p = 0.022) and men overestimated more than women on height (p < 0.001). Reporting errors on weight were increased with overweight status (p < 0.001) and were disproportionate among subgroups. About 27% men and 24% women had reporting errors on weight greater than ± 2.2 kg, and 59% men and 28% women had reporting errors on height greater than 25 mm.

Three-dimensional elastomeric scaffolds designed with cardiac-mimetic structural and mechanical features.

Tissue-engineered constructs, at the interface of material science, biology, engineering, and medicine, have the capacity to improve outcomes for cardiac patients by providing living cells and degradable biomaterials that can regenerate the native myocardium. With an ultimate goal of both delivering cells and providing mechanical support to the healing heart, we designed three-dimensional (3D) elastomeric scaffolds with (1) stiffnesses and anisotropy mimicking explanted myocardial specimens as predicted by finite-element (FE) modeling, (2) systematically varied combinations of rectangular pore pattern, pore aspect ratio, and strut width, and (3) structural features approaching tissue scale. Based on predicted mechanical properties, three scaffold designs were selected from eight candidates for fabrication from poly(glycerol sebacate) by micromolding from silicon wafers. Large 20×20 mm scaffolds with high aspect ratio features (5:1 strut height:strut width) were reproducibly cast, cured, and demolded at a relatively high throughput. Empirically measured mechanical properties demonstrated that scaffolds were cardiac mimetic and validated FE model predictions. Two-layered scaffolds providing fully interconnected pore networks were fabricated by layer-by-layer assembly. C2C12 myoblasts cultured on one-layered scaffolds exhibited specific patterns of cell elongation and interconnectivity that appeared to be guided by the scaffold pore pattern. Neonatal rat heart cells cultured on two-layered scaffolds for 1 week were contractile, both spontaneously and in response to electrical stimulation, and expressed sarcomeric α-actinin, a cardiac biomarker. This work not only demonstrated several scaffold designs that promoted functional assembly of rat heart cells, but also provided the foundation for further computational and empirical investigations of 3D elastomeric scaffolds for cardiac tissue engineering.

Performance and scaling effects in a multilayer microfluidic extracorporeal lung oxygenation device.

Microfluidic fabrication technologies are emerging as viable platforms for extracorporeal lung assist devices and oxygenators for cardiac surgical support and critical care medicine, based in part on their ability to more closely mimic the architecture of the human vasculature than existing technologies. In comparison with current hollow fiber oxygenator technologies, microfluidic systems have more physiologically-representative blood flow paths, smaller cross section blood conduits and thinner gas transfer membranes. These features can enable smaller device sizes and a reduced blood volume in the oxygenator, enhanced gas transfer efficiencies, and may also reduce the tendency for clotting in the system. Several critical issues need to be addressed in order to advance this technology from its current state and implement it in an organ-scale device for clinical use. Here we report on the design, fabrication and characterization of multilayer microfluidic oxygenators, investigating scaling effects associated with fluid mechanical resistance, oxygen transfer efficiencies, and other parameters in multilayer devices. Important parameters such as the fluidic resistance of interconnects are shown to become more predominant as devices are scaled towards many layers, while other effects such as membrane distensibility become less significant. The present study also probes the relationship between blood channel depth and membrane thickness on oxygen transfer, as well as the rate of oxygen transfer on the number of layers in the device. These results contribute to our understanding of the complexity involved in designing three-dimensional microfluidic oxygenators for clinical applications.

Digital 3-d headforms representative of chinese workers.

UNLABELLED: Headforms are useful for designing and testing various types of personal protective equipment used to protect millions of workers from occupational hazards in China. Although the Chinese national standard of head-and-face dimensions for adults was first published in 1981, headforms based on those dimensions were never developed. In 2006, an anthropometric survey of 3000 Chinese civilian workers was conducted. As part of the survey, 350 subjects were scanned with a Cyberware 3D Rapid Digitizer. The manual measurements and 3-D digital scans from this survey were used to develop 3-D digital headforms that represent Chinese workers. OBJECTIVE: The objective of this study was to develop headforms that represent today's Chinese workers. METHODS: Ten facial dimensions relevant to respirator fit were chosen for defining a principal component analysis model which divides the user population into five face size categories. Mean facial dimensions from manual measurements were then computed to target the ideal facial dimensions for each size category. Five scans were chosen from each face size category to be used in the construction process. Selected scans were then averaged to construct a representative headform for each face size category. RESULTS: Five digital 3-D headforms were developed: small, medium, large, long/narrow, and short/wide. These distinct sizes of digital 3-D headforms take into account the linear distance between landmarks as well as the surface contours captured during the 3-D scan. The dimensions of constructed headforms were within approximately 4 mm between the corresponding computed means and manual measurements of anthropometric landmarks for the sample population in each size category. CONCLUSIONS: These new headforms represent the facial size and shape distribution of current Chinese workers and may be useful for respirator research and development. The Chinese medium headform has a wider face width, shorter face length, and smaller nose protrusion when compared with the current U.S. standard headforms. Upon validation, it may be useful to incorporate these dimensions into Chinese and international respiratory protective devices standards.

Validating the acute heart failure index for patients presenting to the emergency department with decompensated heart failure.

BACKGROUND: The acute heart failure index (AHFI) is a previously derived prediction rule to identify patients presenting to emergency departments (ED) with decompensated heart failure (DHF) at low risk of early life-threatening events. STUDY OBJECTIVES: To validate the AHFI prospectively. METHODS: Using a prospective cohort study, adult patients presenting to an urban university hospital ED with DHF were included. Data on 21 variables were gathered to calculate the AHFI. Primary endpoints included inpatient death and non-fatal serious outcomes (myocardial infarction, ventricular fibrillation, cardiogenic shock, cardiac arrest, intubation, or cardiac reperfusion). Secondary endpoints included death from any cause or readmission for heart failure within 30 days. Primary and secondary endpoint rates were calculated with 95% CI for the low and higher-risk subgroups. RESULTS: 259 patients were enrolled. 245/259 (95%) were admitted. 60/259 (23%) met low-risk criteria, of whom 1/60 (1.7%, CI 0.04 to 8.9) was discharged after sustaining pulseless electrical activity arrest. The comparable primary outcome rate in the derivation study was 1.4% (CI 1.1 to 1.7). 17/199 (8.5%, CI 5.1 to 13.3) higher-risk patients experienced an endpoint, compared with 13.3% (CI 12.9 to 13.7) in the derivation cohort. One low-risk patient (1.7%, CI 0.04 to 8.9) died within 30 days, and five (8.3%, CI 2.8 to 18.4) were readmitted. Corresponding rates in the derivation study were 2% and 5%, respectively. CONCLUSION: The results are consistent with those previously reported for the low-risk subgroup of the AHFI. Further research is needed to determine the impact, safety and full range of generalisability of the AHFI as an adjunct to decision making.

A microfluidic respiratory assist device with high gas permeance for artificial lung applications.

One of the principal challenges in artificial lung technology has been the ability to provide levels of oxygen and carbon dioxide exchange that rival those of the natural human lung, while mitigating the deleterious interaction between blood and the surface of the synthetic gas exchange membrane. This interaction is exacerbated by the large oxygenator surface area required to achieve sufficient levels of gas transfer. In an effort to address this challenge, microfluidics-based artificial lung technologies comprising stacked microchannel networks have been explored by several groups. Here we report the design, fabrication and initial testing of a parallel plate multilayered silicone-based microfluidic construct containing ultrathin gas exchange membranes, aimed at maximizing gas transfer efficiency while minimizing membrane-blood contact area. The device comprises a branched microvascular network that provides controlled wall shear stress and uniform blood flow, and is designed to minimize blood damage, thrombosis and inflammatory responses seen in current oxygenators. Initial testing indicates that flow distribution through the multilayer structure is uniform and that the thin membrane can withstand pressures equivalent to those expected during operation. Oxygen transfer using phosphate buffered saline as the carrier fluid has also been assessed, demonstrating a sharp increase in oxygen transfer as membrane thickness is reduced, consistent with the expected values of oxygen permeance for thin silicone membranes.

Combined technologies for microfabricating elastomeric cardiac tissue engineering scaffolds.

Polymer scaffolds that direct elongation and orientation of cultured cells can enable tissue engineered muscle to act as a mechanically functional unit. We combined micromolding and microablation technologies to create muscle tissue engineering scaffolds from the biodegradable elastomer poly(glycerol sebacate). These scaffolds exhibited well defined surface patterns and pores and robust elastomeric tensile mechanical properties. Cultured C2C12 muscle cells penetrated the pores to form spatially controlled engineered tissues. Scanning electron and confocal microscopy revealed muscle cell orientation in a preferential direction, parallel to micromolded gratings and long axes of microablated anisotropic pores, with significant individual and interactive effects of gratings and pore design.

Functional endothelialized microvascular networks with circular cross-sections in a tissue culture substrate.

Functional endothelialized networks constitute a critical building block for vascularized replacement tissues, organ assist devices, and laboratory tools for in vitro discovery and evaluation of new therapeutic compounds. Progress towards realization of these functional artificial vasculatures has been gated by limitations associated with the mechanical and surface chemical properties of commonly used microfluidic substrate materials and by the geometry of the microchannels produced using conventional fabrication techniques. Here we report on a method for constructing microvascular networks from polystyrene substrates commonly used for tissue culture, built with circular cross-sections and smooth transitions at bifurcations. Silicon master molds are constructed using an electroplating process that results in semi-circular channel cross-sections with smoothly varying radii. These master molds are used to emboss polystyrene sheets which are then joined to form closed bifurcated channel networks with circular cross-sections. The mechanical and surface chemical properties of these polystyrene microvascular network structures enable culture of endothelial cells along the inner lumen. Endothelial cell viability was assessed, documenting nearly confluent monolayers within 3D microfabricated channel networks with rounded cross-sections.

Acculturation among three racial/ethnic groups of host and immigrant adolescents.

This study compares Latino host, Latino immigrant, Asian-American host, Asian-American immigrant and European-American host groups of adolescents with respect to four acculturation-related variables: ethnic identity exploration, ethnic identity affirmation/belonging, outgroup orientation, and American identity. Using the five ethno-generational categories as a grouping variable, we conducted analyses of 313 survey responses to the acculturation items at two time periods, 9 weeks apart. Results showed that differences among the three host racial/ethnic groups can best be explained by a group dominance perspective, whereby the two racial/ethnic minority groups are more similar to each other than they are to the European-American group. Furthermore, the relationship between American identity and ethnic identity components is stronger among the three host groups, as compared to the immigrant groups. Implications for future research with adolescent members of the host group whose heritage culture is non-European are drawn.