Smart Hydrogel Swelling State Detection Based on a Power-Transfer Transduction Principle.

Stimulus-responsive (smart) hydrogels are a promising sensing material for biomedical contexts due to their reversible swelling change in response to target analytes. The design of application-specific sensors that utilize this behavior requires the development of suitable transduction concepts. The presented study investigates a power-transfer-based readout approach that is sensitive to small volumetric changes of the smart hydrogel. The concept employs two thin film polyimide substrates with embedded conductive strip lines, which are shielded from each other except at the tip region, where the smart hydrogel is sandwiched in between. The hydrogel's volume change in response to a target analyte alters the distance and orientation of the thin films, affecting the amount of transferred power between the two transducer parts and, consequently, the measured sensor output voltage. With proper calibration, the output signal can be used to determine the swelling change of the hydrogel and, consequently, to quantify the stimulus. In proof-of-principle experiments with glucose- and pH-sensitive smart hydrogels, high sensitivity to small analyte concentration changes was found along with very good reproducibility and stability. The concept was tested with two exemplary hydrogels, but the transduction principle in general is independent of the specific hydrogel material, as long as it exhibits a stimulus-dependent volume change. The application vision of the presented research is to integrate in situ blood analyte monitoring capabilities into standard (micro)catheters. The developed sensor is designed to fit into a catheter without obstructing its normal use and, therefore, offers great potential for providing a universally applicable transducer platform for smart catheter-based sensing.

Viscoelastic Particle Focusing and Separation in a Spiral Channel.

As one type of non-Newtonian fluid, viscoelastic fluids exhibit unique properties that contribute to particle lateral migration in confined microfluidic channels, leading to opportunities for particle manipulation and separation. In this paper, particle focusing in viscoelastic flow is studied in a wide range of polyethylene glycol (PEO) concentrations in aqueous solutions. Polystyrene beads with diameters from 3 to 20 µm are tested, and the variation of particle focusing position is explained by the coeffects of inertial flow, viscoelastic flow, and Dean flow. We showed that particle focusing position can be predicted by analyzing the force balance in the microchannel, and that particle separation resolution can be improved in viscoelastic flows.

Multiple-Streams Focusing-Based Cell Separation in High Viscoelasticity Flow.

Viscoelastic flow has been widely used in microfluidic particle separation processes, in which particles get focused on the channel center in diluted viscoelastic flow. In this paper, the transition from single-stream focusing to multiple-streams focusing (MSF) in high viscoelastic flow is observed, which is applied for cell separation processes. Particle focusing stream bifurcation is caused by the balance between elastic force and viscoelastic secondary flow drag force. The influence of cell physical properties, such as cell dimension, shape, and deformability, on the formation of multiple-streams focusing is studied in detail. Particle separation is realized utilizing different separation criteria. The size-based separation of red (RBC) and white (WBC) blood cells is demonstrated in which cells get focused in different streams based on their dimension difference. Cells with different deformabilities get stretched in the viscoelastic flow, leading to the change of focusing streams, and this property is harnessed to separate red blood cells infected with the malaria parasite, Plasmodium falciparum. The achieved results promote our understanding of particle movement in the high viscoelastic flow and enable new particle manipulation and separation processes for sample treatment in biofluids.

Polypeptide grafted hyaluronan: A self-assembling comb-branched polymer constructed from biological components.

Rheological evidence is provided demonstrating that covalent grafting of monodisperse isotactic poly(L-leucine) branches onto linear hyaluronan (HA) polysaccharide chains yields comb-branched HA chains that self-assemble into long-lived physical networks in aqueous solutions driven by hydrophobic interactions between poly(L-leucine) chains. This is in stark contrast to native (unmodified) HA solutions which exhibit no tendency to form long-lived physical networks.

In Vivo Monitoring of Glucose Using Ultrasound-Induced Resonance in Implantable Smart Hydrogel Microstructures.

A novel glucose sensor is presented using smart hydrogels as biocompatible implantable sensing elements, which eliminates the need for implanted electronics and uses an external medical-grade ultrasound transducer for readout. The readout mechanism uses resonance absorption of ultrasound waves in glucose-sensitive hydrogels. In vivo glucose concentration changes in the interstitial fluid lead to swelling or deswelling of the gels, which changes the resonance behavior. The hydrogels are designed and shaped such as to exhibit specific mechanical resonance frequencies while remaining sonolucent to other frequencies. Thus, they allow conventional and continued ultrasound imaging, while yielding a sensing signal at specific frequencies that correlate with glucose concentration. The resonance frequencies can be tuned by changing the shape and mechanical properties of the gel structures, such as to allow for multiple, colocated implanted hydrogels with different sensing characteristics or targets to be employed and read out, without interference using the same ultrasound transducer, by simply toggling frequencies. The fact that there is no need for any implantable electronics, also opens up the path toward future use of biodegradable hydrogels, thus creating a platform that allows injection of sensors that do not need to be retrieved when they reach the end of their useful lifespan.

Catheter-mounted smart hydrogel ultrasound resonators for intravenous analyte monitoring.

Continuous monitoring of drug concentrations in blood plasma can be beneficial to guide individualized drug administration. High interpatient variability in required dosage and a small therapeutic window of certain drugs, such as anesthetic medications, can cause risks and challenges in accurate dosing during administration. In this work, we present a sensing platform concept using a smart hydrogel micro resonator sheet with medical ultrasound readout that is integrated on the top of a catheter. This concept is validated in-vitro using glucose as an easy to access and handle target analyte. In the case of continuous glucose measurement, our novel catheter-mounted sensing platform allows the detection of glucose concentrations in the range of 0 mM to 12 mM. While these experiments use a well-known glucose-sensitive smart hydrogel for proof-of-principle experiments, this new sensing platform is intended to provide the basis for continuous monitoring of various intravenously applied medications. Selectivity to different drugs, e.g., fentanyl, can be accomplished by developing a corresponding smart hydrogel composition.Clinical Relevance- Many intravenous medications, especially anesthetics, show considerable pharmacokinetic inter-subject variability. Continuous monitoring of intravenous analyte concentrations would enable individualizing the administration of these drugs to the specific patient.

Thermally tunable hydrogel crosslinking mediated by temperature sensitive liposome.

Hydrogel crosslinking by external stimuli is a versatile strategy to control and modulate hydrogel properties. Besides photonic energy, thermal energy is one of the most accessible external stimuli and widely applicable for many biomedical applications. However, conventional thermal crosslinking systems require a relatively high temperature (over 100 °C) to initiate covalent bond formation. To our knowledge, there has not been a thermally tunable hydrogel crosslinking system suitable for biological applications. This work demonstrates a unique approach to utilize temperature sensitive liposomes to control and modulate hydrogel crosslinking over mild temperature range (below 50 °C). Temperature sensitive liposomes were used to control the release of chemical crosslinkers by moderate temperature changes. The thermally controlled crosslinker release resulted in tunable mechanical and transport properties of the hydrogel. No significant inflammable response observed in the histology results ensured the biocompatibility of the liposome-mediated crosslinkable hydrogel. This work opens new opportunities to implement thermal energy system for control and modulate hydrogel properties.

Comparison of surfactants used to prepare aqueous perfluoropentane emulsions for pharmaceutical applications.

Perfluoropentane (PFP), a very hydrophobic, nontoxic, noncarcinogenic fluoroalkane, has generated much interest in biomedical applications, including occlusion therapy and controlled drug delivery. For most of these applications, the dispersion within aqueous media of a large quantity of PFP droplets of the proper size is critically important. Surprisingly, the interfacial tension of PFP against water in the presence of surfactants used to stabilize the emulsion has rarely, if ever, been measured. In this study, we report the interfacial tension of PFP in the presence of surfactants used in previous studies to produce emulsions for biomedical applications: polyethylene oxide-co-polylactic acid (PEO-PLA) and polyethylene oxide-co-poly-epsilon-caprolactone (PEO-PCL). Because both of these surfactants are uncharged diblock copolymers that rely on the mechanism of steric stabilization, we also investigate for comparison's sake the use of the small-molecule cationic surfactant cetyl trimethyl ammonium bromide (CTAB) and the much larger protein surfactant bovine serum albumin (BSA). The results presented here complement previous reports of the PFP droplet size distribution and will be useful for determining to what extent the interfacial tension value can be used to control the mean PFP droplet size.

A comparison of fluoroalkyl-derivatized imidazolium:TFSI and alkyl-derivatized imidazolium:TFSI ionic liquids: a molecular dynamics simulation study.

Molecular dynamics simulations of fluoroalkyl-derivatized imidazolium:bis(trifluoromethylsulfonyl)imide (TFSI) room temperature ionic liquids (FADI-RTILs) with cations of the structure 1-F(CF(2))(n)(CH(2))(2)-3-methyl imidazolium have been performed and compared with simulations of alkyl-derivatized 1-H(CH(2))(n+2)-3-methyl imidazolium analogs (ADI-RTILs). Simulations yield RTIL densities, viscosities and ionic conductivities for the FADI-RTILs and ADI-RTILs in reasonably good agreement with experimental data. Partial fluorination results in a larger increase in density than would be anticipated based upon the density difference between perfluoralkane and alkane melts. Similarly, the slowing down in dynamics upon partial fluorination is greater than would be expected based upon the increase in cation volume. Examination of cation-cation, anion-anion and cation-anion centers-of-mass radial distribution functions reveal remarkably little influence of partial fluorination on the spherically averaged intermolecular structure of the RTILs. Similarly, simulations reveal little change in tail conformations and the extent of tail-tail aggregation upon partial fluorination. The interaction of the TFSI anion with the positively charged imidazolium ring hydrogen and nitrogen atoms is also little influenced by partial fluorination. However, the partially fluorinated alkyl tail exhibits increased interaction with the TFSI anion due to the electron withdrawing character of the fluorinated groups. We believe this strong tail-anion electrostatic interaction largely accounts for the higher than expected density and slower than expected dynamics in the FADI-RTILs.

Smart Hydrogel Micromechanical Resonators with Ultrasound Readout for Biomedical Sensing.

One of the main challenges for implantable biomedical sensing schemes is obtaining a reliable signal while maintaining biocompatibility. In this work, we demonstrate that a combination of medical ultrasound imaging and smart hydrogel micromechanical resonators can be employed for continuous monitoring of analyte concentrations. The sensing principle is based on the shift of the mechanical resonance frequencies of smart hydrogel structures induced by their volume-phase transition in response to changing analyte levels. This shift can then be measured as a contrast change in the ultrasound images due to resonance absorption of ultrasound waves. This concept eliminates the need for implanting complex electronics or employing transcutaneous connections for sensing biomedical analytes in vivo. Here, we present proof-of-principle experiments that monitor in vitro changes in ionic strength and glucose concentrations to demonstrate the capabilities and potential of this versatile sensing platform technology.

Separation of the effects of pH and polymer concentration on the swelling pressure and elastic modulus of a pH-responsive hydrogel.

The elastic shear modulus G and swelling pressure ω are studied for a basic, pH-responsive hydrogel synthesized by crosslinking copolymerization of co-monomers hydroxypropyl methacrylate and N,N-dimethylaminoethyl methacrylate with crosslinker tetraethylene glycol dimethacrylate. Under normal conditions of use as a "smart" material, hydrogel swelling ratio Q and pH vary simultaneously, but here G and ω values are presented as a function of pH with Q held constant and vice-versa. At fixed pH, G decreases with increase in Q in a power law dependence, as predicted by the Flory-Rehner model. However, at fixed Q, G increases with decrease in pH (i.e, increase in degree of ionization). The pH effect is more pronounced than the volume effect, thus the hydrogel stiffens as it swells in response to pH change. At high pH, ω values of the uncharged hydrogel obey the Flory-Rehner model, whereas explicit ionic contributions can be identified at lower pH values.

Fabrication of highly uniform nanoparticles from recombinant silk-elastin-like protein polymers for therapeutic agent delivery.

Here we generate silk-elastin-like protein (SELP) polymeric nanoparticles and demonstrate precise control over their dimensions using an electrospray differential mobility analyzer (ES-DMA). Electrospray produces droplets encompassing several polymer strands. Evaporation ensues, leading polymer strands to accumulate at the droplet interface, forming a hollow nanoparticle. The resulting nanoparticle size distributions, which govern particle yield, depend on buffer concentration to the -1/3 power, polymer concentration to the 1/3 power, and ratio of silk-to-elastin blocks. Three recombinantly tuned ratios of 8:16, 4:8, and 4:16, respectively named SELP-815K, SELP-47K, and SELP-415K, are employed, with the latter ratio resulting in a thinner shell and larger diameter for the nanoparticles than the former. The DMA narrows the size distribution by electrostatically classifying the aerosolized nanoparticles. These highly uniform nanoparticles have variations of 1.2 and 1.4 nm for 24.0 and 36.0 nm particles, respectively. Transmission electron microscopy reveals the nanoparticles to be faceted, as a buckling instability releases compression energy arising from evaporation after the shell has formed by bending it. A thermodynamic equilibrium exists between compression and bending energies, where the facet length is half the particle diameter, in agreement with experiments. Rod-like particles also formed from polymer-stabilized filaments when the viscous length exceeds the jet radius at higher solution viscosities. The unusual uniformity in composition and dimension indicates the potential of these nanoparticles to deliver bioactive and imaging agents.

Effect of temperature changes on the performance of ionic strength biosensors based on hydrogels and pressure sensors.

Stimuli responsive hydrogels show a strong ability to change in volume with changes in selected environmental properties. This tendency of these hydrogels to change in volume is captured as pressure-change in confined cavities of pressure sensors. An array of pressure sensors on a single chip may carry hydrogels sensitive to multiple, selected metabolic markers and continuously monitor multiple vital parameters simultaneously. Currently, such sensors are capable of continuously monitoring pH, ionic strength, glucose levels and temperature in the sensor environment. In this paper, we report the effect of temperature changes on the performance of ionic strength sensor. A formulation of hydrogel that renders it sensitive to changes in ionic strength was UV polymerized in situ in piezoresistive pressure sensors with different membrane sizes. The sensor sensitivity, response time and stability are investigated as a function of temperature in vitro. The effect of temperature on these sensor characteristics is discussed.

Smart hydrogel based microsensing platform for continuous glucose monitoring.

In this paper, we present preliminary results showing the response of glucose-sensitive hydrogels, confined in micro-pressure sensors, to the changes in environmental glucose concentration. The glucose concentrations were incrementally varied between 20 and 0mM in 0.15M PBS solution at 7.4 pH and bovine serum at 7.4 pH at room temperature and response of the sensor was recorded. The micro sensors demonstrate a response time of 10 minutes in both PBS and serum. Tissue response after 55 days of subcutaneous implantation of a EtO sterilized sensor in mice is presented. The preliminary analysis of the surrounding tissue shows inflammation which is believed not to interfere with the sensor performance.

Rheological properties of cross-linked hyaluronan-gelatin hydrogels for tissue engineering.

Hydrogels that mimic the natural extracellular matrix (ECM) are used in three-dimensional cell culture, cell therapy, and tissue engineering. A semi-synthetic ECM based on cross-linked hyaluronana offers experimental control of both composition and gel stiffness. The mechanical properties of the ECM in part determine the ultimate cell phenotype. We now describe a rheological study of synthetic ECM hydrogels with storage shear moduli that span three orders of magnitude, from 11 to 3 500 Pa, a range important for engineering of soft tissues. The concentration of the chemically modified HA and the cross-linking density were the main determinants of gel stiffness. Increase in the ratio of thiol-modified gelatin reduced gel stiffness by diluting the effective concentration of the HA component.

In-vitro investigations of a pH- and ionic-strength-responsive polyelectrolytic hydrogel using a piezoresistive microsensor.

Environmental responsive or smart hydrogels show a volume phase transition due to changes of external stimuli such as pH or ionic strength of an ambient solution. Thus, they are able to convert reversibly chemical energy into mechanical energy and therefore they are suitable as sensitive material for integration in biochemical microsensors and MEMS devices. In this work, micro-fabricated silicon pressure sensor chips with integrated piezoresistors were used as transducers for the conversion of mechanical work into an appropriate electrical output signal due to the deflection of a thin silicon bending plate. Within this work two different sensor designs have been studied. The biocompatible poly(hydroxypropyl methacrylate-N,N-dimethylaminoethyl methacrylate-tetra-ethyleneglycol dimethacrylate) (HPMA-DMA-TEGDMA) was used as an environmental sensitive element in piezoresistive biochemical sensors. This polyelectrolytic hydrogel shows a very sharp volume phase transition at pH values below about 7.4 which is in the range of the physiological pH. The sensor's characteristic response was measured in-vitro for changes in pH of PBS buffer solution at fixed ionic strength. The experimental data was applied to the Hill equation and the sensor sensitivity as a function of pH was calculated out of it. The time-dependent sensor response was measured for small changes in pH, whereas different time constants have been observed. The same sensor principal was used for sensing of ionic strength. The time-dependent electrical sensor signal of both sensors was measured for variations in ionic strength at fixed pH value using PBS buffer solution. Both sensor types showed an asymmetric swelling behavior between the swelling and the deswelling cycle as well as different time constants, which was attributed to the different nature of mechanical hydrogel-confinement inside the sensor.

Low-frequency dilational elasticity of the nematic 4'-pentyl-4-biphenylcarbonitrile (5CB)/water interface.

Axisymmetric oscillating pendant drop shape analysis has been used to study the interfacial rheology of the liquid crystal 4'-pentyl-4-biphenylcarbonitrile (5CB) in water with homeotropic anchoring. Nearly spherical 5CB droplets were subjected to low frequency (1-5 mHz) volume oscillations, and the increase in tension with surface dilation was used to calculate the complex modulus. The droplet interface response is completely elastic, with no relaxations occurring on the experimental time scale. This surprising result is attributed to droplet storage of elastic energy in the form of distorted orientational distributions within the bulk (Frank elasticity) and on the surface (anchoring elasticity).

A novel mesophase formed by top-shaped molecules in the bulk and unsupported thin films: a molecular dynamics study.

We have used molecular dynamics simulations to investigate the ordering of top-shaped molecules in bulk phases and in unsupported thin films. Each rigid anisotropic molecule was composed of 11 Lennard-Jones interaction centers (beads). In an attempt to enhance the nematic stability in preference to smectic, the three central beads were assigned a larger Lennard-Jones diameter than the tail beads, giving the molecule a shape resembling a top. The molecular model was found to exhibit an unusual bulk mesophase with long-range orientational order and with molecular center-of-mass positions arranged in parallel interdigitated layers, with layer spacing smaller than half the length of the long axis of a molecule. However, despite the toplike molecular shape, no nematic phase was observed in the pressure range studied. Unsupported films of the isotropic liquid were cooled in order to locate a triple point between the novel mesophase, vapor, and isotropic liquid. At temperatures slightly above the triple point, enhanced surface ordering of molecules was found to occur in the unsupported film. At temperatures slightly below the triple point, the preferred molecular alignment in the unsupported film was parallel to the interface, in violation of arguments that have been proposed based on the relative enthalpies of various cleavage planes for close-packed structures.

Interfacial tension of a nematic liquid crystal/water interface with homeotropic surface alignment.

Pendant drop experimental results are presented for the temperature dependence of the interfacial tension between water and the immiscible nematic liquid crystal 4'-pentyl-4-biphenylcarbonitrile (5CB) in the presence of the adsorbed surfactant cetyltrimethylammonium bromide (CTAB). Adsorption of the surfactant lowers the interfacial tension value and is also known from earlier work to induce a transition in liquid crystal surface alignment from planar to homeotropic [Brake et al. Langmuir 2003, 19, 6436.]. Discrepancies exist in the literature regarding the density of 5CB, and the density difference between 5CB and water in any case is very small. However, from the ability to form pendant 5CB drops, one may infer that the density of 5CB exceeds that of water over the entire temperature range studied (28-41 degrees C), in disagreement with the predictions of one earlier report on 5CB. The interfacial tension is shown to exhibit a relative maximum near the bulk 5CB nematic-isotropic transition temperature T(NI), regardless of which published data set of 5CB density values is used to analyze the measurements, with a possible discontinuity in tension occurring at T(NI). The anomalous shape of the interfacial tension curve, depending on the choice of the 5CB density data set, may be quite similar to that recently reported for the interface between 5CB and a hydrophobic, isotropic molten polymer (Rai et al. Langmuir 2003, 19, 7370).