Controlling Colloidal Crystal Nucleation and Growth with Photolithographically Defined Templates.

Colloidal crystallization provides a means to synthesize hierarchical nanostructures by design and to use these complex structures for nanodevice fabrication. In particular, DNA provides a means to program interactions between particles with high specificity, thereby enabling the formation of particle superlattice crystallites with tailored unit cell geometries and surface faceting. However, while DNA provides precise control of particle-particle bonding interactions, it does not inherently present a means of controlling higher-level structural features such as the size, shape, position, or orientation of a colloidal crystallite. While altering assembly parameters such as temperature or concentration can enable limited control of crystallite size and geometry, integrating colloidal assemblies into nanodevices requires better tools to manipulate higher-order structuring and improved understanding of how these tools control the fundamental kinetics and mechanisms of colloidal crystal growth. In this work, photolithography is used to produce patterned substrates that can manipulate the placement, size, dispersity, and orientation of colloidal crystals. By adjusting aspects of the pattern, such as feature size and separation, we reveal a diffusion-limited mechanism governing crystal nucleation and growth. Leveraging this insight, patterns are designed that can produce wafer-scale substrates with arrays of nanoparticle superlattices of uniform size and shape. These design principles therefore bridge a gap between a fundamental understanding of nanoparticle assembly and the fabrication of nanostructures compatible with functional devices.

Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence.

Hepatic encephalopathy (HE) is a challenging complication of liver disease that is associated with substantial morbidity and mortality. Branched-chain amino acid (BCAA) supplementation in the management of HE is a debated topic. This narrative review aims to provide an up-to-date review of the topic and includes studies featuring patients with hepatocellular carcinoma. A review of the literature was performed using the online databases MEDLINE and EMBASE for studies between 2002 and December 2022. Keywords 'branched-chain amino acids', 'liver cirrhosis' and 'hepatic encephalopathy' were used. Studies were assessed for inclusion and exclusion criteria. Of 1045 citations, 8 studies met the inclusion criteria. The main outcomes reported for HE was changed in minimal HE (MHE) (n = 4) and/or incidence of overt HE (OHE) (n = 7). Two of the 4 studies reporting on MHE had improvement in psychometric testing in the BCAA group, but there was no change in the incidence of OHE in any of the 7 papers in the BCAA group. There were few adverse effects of BCAA supplementation. This review found weak evidence for BCAA supplementation for MHE, and no evidence for BCAAs for OHE. However, given the relative paucity and methodological heterogeneity of the current research, there is scope for future studies to examine the effects of varying timing, dosage, and frequency of BCAAs on outcomes such as HE. Importantly, research is also needed to examine BCAAs in conjunction with standard therapies for HE such as rifaximin and/or lactulose.

A Clinical-Scale Microfluidic Respiratory Assist Device with 3D Branching Vascular Networks.

Recent global events such as COVID-19 pandemic amid rising rates of chronic lung diseases highlight the need for safer, simpler, and more available treatments for respiratory failure, with increasing interest in extracorporeal membrane oxygenation (ECMO). A key factor limiting use of this technology is the complexity of the blood circuit, resulting in clotting and bleeding and necessitating treatment in specialized care centers. Microfluidic oxygenators represent a promising potential solution, but have not reached the scale or performance required for comparison with conventional hollow fiber membrane oxygenators (HFMOs). Here the development and demonstration of the first microfluidic respiratory assist device at a clinical scale is reported, demonstrating efficient oxygen transfer at blood flow rates of 750 mL min⁻1 , the highest ever reported for a microfluidic device. The central innovation of this technology is a fully 3D branching network of blood channels mimicking key features of the physiological microcirculation by avoiding anomalous blood flows that lead to thrombus formation and blood damage in conventional oxygenators. Low, stable blood pressure drop, low hemolysis, and consistent oxygen transfer, in 24-hour pilot large animal experiments are demonstrated - a key step toward translation of this technology to the clinic for treatment of a range of lung diseases.

Self-Assembling Systems for Optical Out-of-Plane Coupling Devices.

Micromirrors are used in integrated photonics to couple extraplanar light into the planar structure of a device by redirecting light via specular reflection. Compared with grating or prism-based couplers, micromirrors allow for coupling of light over a broader range of wavelengths, provided that the micromirror is fabricated with a specific 3D shape to ensure proper reflection angles. In principle, self-assembly methods could enable reliable, parallelizable fabrication of such devices with a high degree of precision by designing self-assembling components that produce the desired microscale geometry as their thermodynamic products. In this work, we use DNA-functionalized nanoparticles to assemble faceted crystallites with predetermined crystal shapes, and demonstrate with microscale retroreflectance measurements that these self-assembled nanoparticle arrays do indeed behave like optically flat mirrors. Furthermore, we show that the tilt angle of the micromirrors can be intentionally controlled by altering the crystallographic symmetry and preferred crystal orientations as a function of the self-assembly process, thereby altering the resulting specular angle in a programmable manner. Measurements of optical coupling from normal incidence into the substrate plane via an optical fiber confirm that the faceted structures can function as optical out-of-plane coupling devices, and coating these structures with reflective materials allows for high efficiency of light reflection in addition to the angular control. Together, these experiments demonstrate how self-assembled nanoparticle materials can be used to generate optically relevant architectures, enabling a significant step in the development of self-assembly as a materials fabrication tool for integrated optical devices.

Multilayer Scaling of a Biomimetic Microfluidic Oxygenator.

Extracorporeal membrane oxygenation (ECMO) has been advancing rapidly due to a combination of rising rates of acute and chronic lung diseases as well as significant improvements in the safety and efficacy of this therapeutic modality. However, the complexity of the ECMO blood circuit, and challenges with regard to clotting and bleeding, remain as barriers to further expansion of the technology. Recent advances in microfluidic fabrication techniques, devices, and systems present an opportunity to develop new solutions stemming from the ability to precisely maintain critical dimensions such as gas transfer membrane thickness and blood channel geometries, and to control levels of fluid shear within narrow ranges throughout the cartridge. Here, we present a physiologically inspired multilayer microfluidic oxygenator device that mimics physiologic blood flow patterns not only within individual layers but throughout a stacked device. Multiple layers of this microchannel device are integrated with a three-dimensional physiologically inspired distribution manifold that ensures smooth flow throughout the entire stacked device, including the critical entry and exit regions. We then demonstrate blood flows up to 200 ml/min in a multilayer device, with oxygen transfer rates capable of saturating venous blood, the highest of any microfluidic oxygenator, and a maximum blood flow rate of 480 ml/min in an eight-layer device, higher than any yet reported in a microfluidic device. Hemocompatibility and large animal studies utilizing these prototype devices are planned. Supplemental Visual Abstract, http://links.lww.com/ASAIO/A769.

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.

Toward Development of a Higher Flow Rate Hemocompatible Biomimetic Microfluidic Blood Oxygenator.

The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability to scale these devices to clinically relevant blood flow rates, in part because the typically very low blood flow in a single layer of a microfluidic oxygenator device requires stacking of a logistically challenging number of layers. We have developed biomimetic microfluidic oxygenators for the past decade and report here on the development of a high-flow (30 mL/min) single-layer prototype, scalable to larger structures via stacking and assembly with blood distribution manifolds. Microfluidic oxygenators were designed with biomimetic in-layer blood distribution manifolds and arrays of parallel transfer channels, and were fabricated using high precision machined durable metal master molds and microreplication with silicone films, resulting in large area gas transfer devices. Oxygen transfer was evaluated by flowing 100% O2 at 100 mL/min and blood at 0-30 mL/min while monitoring increases in O2 partial pressures in the blood. This design resulted in an oxygen saturation increase from 65% to 95% at 20 mL/min and operation up to 30 mL/min in multiple devices, the highest value yet recorded in a single layer microfluidic device. In addition to evaluation of the device for blood oxygenation, a 6-h in vitro hemocompatibility test was conducted on devices (n = 5) at a 25 mL/min blood flow rate with heparinized swine donor blood against control circuits (n = 3). Initial hemocompatibility results indicate that this technology has the potential to benefit future applications in extracorporeal lung support technologies for acute lung injury.

Dynamic Manipulation of DNA-Programmed Crystals Embedded in a Polyelectrolyte Hydrogel.

DNA is a powerful tool for programming the three-dimensional organization of nanomaterials, where the specificity of nucleotide base-pairing can enable precise, complex, and dynamically addressable structures like colloidal crystals. However, because these DNA-programmed materials are often only stable in solution, their organization can be easily disrupted by changes to its local environment. Methods to stabilize these materials have been developed, but often come at the expense of altering or permanently fixing the materials' structures, removing many of the benefits of using DNA interactions to program assembly. Thus, these methods limit the application of DNA-assembled structures as dynamic and programmable material components. Here, a method is presented to resolve these drawbacks for DNA-grafted nanoparticles, also known as Programmable Atom Equivalents (PAEs), by embedding assembled lattices within a hydrogel matrix. The preformed lattices are exposed to polymerizable residues that electrostatically bind to the charged backbone of the DNA ligands and form a continuous, permeating gel network that stabilizes the colloidal crystals upon introduction of a radical initiator. After embedding PAEs in a hydrogel, deformation of the macroscopic matrix results in concomitant deformation of the PAE lattices, allowing superlattice structural changes to be induced by chemical methods (such as changing solute concentration to alter swelling pressure) or by application of mechanical strain. Changes to the structure of the PAE lattices are reversible and repeatable over multiple cycles and can be either isotropic (such as by swelling) or anisotropic (such as by mechanical deformation). This method of embedding nanoparticle crystals inside of a flexible and environmentally responsive hydrogel is therefore a useful tool in extending the utility of PAEs and other micro- and nanostructures assembled with DNA.

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.

Using DNA to Control the Mechanical Response of Nanoparticle Superlattices.

Nanoparticle superlattice assembly has been proposed as an ideal means of programming material properties as a function of hierarchical organization of different building blocks. While many investigations have focused on electromagnetic, optical, and transport behaviors, nanoscale self-assembly via supramolecular interactions is also a potentially desirable method to program material mechanical behavior, as it allows the strength and three-dimensional organization of chemical bonds to be used as handles to manipulate how a material responds to external stress. DNA-grafted nanoparticles are a particularly promising building block for such hierarchically organized materials because of DNA's tunable and nucleobase sequence-specific complementary binding. Using nanoindentation, we show here that the programmability of oligonucleotide interactions allows the modulus of DNA-grafted nanoparticle superlattices to be easily tuned overly nearly 2 orders of magnitude. Additionally, we demonstrate that alterations to the supramolecular bond strength between particles can alter how a lattice deforms under applied mechanical force. As a result, the superlattices can be programmed either to reorganize their internal structures to dissipate mechanical energy or to completely recover their initial structure upon relaxation, independently of how the particles are arranged in 3D space. These behaviors are subsequently explained as a function of the hierarchical structure of the DNA-guided assemblies by using a simple truss-structure model. Altering the supramolecular DNA connections between particles therefore provides a simple and rational means of dictating different aspects of material mechanical response to produce tailorable properties that are not typically observed in conventional bulk materials. Ultimately, these studies enable control over the deformation behavior of future DNA-assembled nanomaterials and provide evidence that supramolecular chemistry is an effective tool in controlling the mechanical properties of nanomaterials as a function of their hierarchical design.

Single-crystal Winterbottom constructions of nanoparticle superlattices.

Colloidal nanoparticle assembly methods can serve as ideal models to explore the fundamentals of homogeneous crystallization phenomena, as interparticle interactions can be readily tuned to modify crystal nucleation and growth. However, heterogeneous crystallization at interfaces is often more challenging to control, as it requires that both interparticle and particle-surface interactions be manipulated simultaneously. Here, we demonstrate how programmable DNA hybridization enables the formation of single-crystal Winterbottom constructions of substrate-bound nanoparticle superlattices with defined sizes, shapes, orientations and degrees of anisotropy. Additionally, we show that some crystals exhibit deviations from their predicted Winterbottom structures due to an additional growth pathway that is not typically observed in atomic crystals, providing insight into the differences between this model system and other atomic or molecular crystals. By precisely tailoring both interparticle and particle-surface potentials, we therefore can use this model to both understand and rationally control the complex process of interfacial crystallization.

DNA-Directed Non-Langmuir Deposition of Programmable Atom Equivalents.

Particle assembly at interfaces via programmed DNA interactions allows for independent modification of both nanoparticle-surface interaction strength and the magnitude of interparticle repulsion. Together, these factors allow for modification of the deposited thin film morphology via alterations in DNA binding sequence. Importantly, both Langmuir and random sequential adsorption models yield insights into the thermodynamics of deposition but cannot fully explain particle coverage as a function of all relevant variables, indicating that the particle deposition mechanism for DNA-grafted colloids is more complex than prior adsorption phenomena. Here, it is shown that these deviations from standard behavior arise from the fact that each nanoparticle is attached to the surface via multiple weak DNA duplex interactions, enabling diffusion of adsorbed colloids across the substrate. Thus, surface migration of individual particles causes reorganization of the deposited monolayer, leading to the unusual behavior of coverage increasing at elevated temperatures that are just below the particle desorption temperature. The programmability of DNA-directed particle deposition therefore allows for precise control over the morphology of monolayer films, as well as the ability to generate crystalline materials with controllable surface roughness and grain size through layer-by-layer growth. The increased control over thin film morphology potentially enables tailoring of mechanical and optical properties and holds promise for use in a variety of applications.

Aligned carbon nanotube array stiffness from stochastic three-dimensional morphology.

The landmark theoretical properties of low dimensional materials have driven more than a decade of research on carbon nanotubes (CNTs) and related nanostructures. While studies on isolated CNTs report behavior that aligns closely with theoretical predictions, studies on cm-scale aligned CNT arrays (>10(10) CNTs) oftentimes report properties that are orders of magnitude below those predicted by theory. Using simulated arrays comprised of up to 10(5) CNTs with realistic stochastic morphologies, we show that the CNT waviness, quantified via the waviness ratio (w), is responsible for more than three orders of magnitude reduction in the effective CNT stiffness. Also, by including information on the volume fraction scaling of the CNT waviness, the simulation shows that the observed non-linear enhancement of the array stiffness as a function of the CNT close packing originates from the shear and torsion deformation mechanisms that are governed by the low shear modulus (∼1 GPa) of the CNTs.

Regional network of magnetic resonance imaging gray matter volume in healthy aging.

Healthy aging has been associated with brain volume reductions preferentially affecting the frontal cortex, but also involving other regions. We used a network model of regional covariance, the Scaled Subprofile Model, with magnetic resonance imaging voxel-based morphometry to identify the regional distribution of gray matter associated with aging in 26 healthy adults, 22-77 years old. Scaled Subprofile Model analysis identified a pattern that was highly correlated with age (R2=0.66, P