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.

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.

Evaluating the influence of particle morphology and density on the viscosity and injectability of a novel long-acting local anesthetic suspension.

Proper pain management is well understood to be one of the fundamental aspects of a healthy postoperative recovery in conjunction with mobility and nutrition. Approximately, 10% of patients prescribed opioids after surgery continue to use opioids in the long-term and as little as 10 days on opioids can result in addiction. In an effort to provide physicians with an alternative pain management technique, this work evaluates the material properties of a novel local anesthetic delivery system designed for controlled release of bupivacaine for 72 hours. The formulation utilizes solid-lipid microparticles that encapsulate the hydrophobic molecule bupivacaine in its free-base form. The lipid microparticles are suspended in a non-crosslinked hyaluronic acid hydrogel, which acts as the microparticle carrier. Two different particle manufacturing techniques, milling and hot homogenization, were evaluated in this work. The hot homogenized particles had a slower and more controlled release than the milled particles. Rheological techniques revealed that the suspension remains a viscoelastic fluid when loaded with either particle type up to 25% (w/v) particles densities. Furthermore, the shear thinning properties of the suspension media, hyaluronic acid hydrogel, were conserved when bupivacaine-loaded solid-lipid microparticles were loaded up to densities of 25% (w/v) particle loading. The force during injection was measured for suspension formulations with varying hyaluronic acid hydrogel concentrations, particle densities, particle types and particle sizes. The results indicate that the formulation viscosity is highly dependent on particle density, but hyaluronic acid hydrogel is required for lowering injection forces as well as minimizing clogging events.

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.

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.

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.

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.

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.

Viscoelastic second normal stress difference dominated multiple-stream particle focusing in microfluidic channels.

Particle focusing in viscoelastic fluid flow is a promising approach for inducing particle separations in microfluidic devices. The results from theoretical studies indicated that multiple stream particle focusing can be realized with a large magnitude of the elastic second normal stress difference (N2). For dilute polymer solutions, theoretical and experimental studies show that the magnitude of N2 is never large, no matter how large the polymer molecular weight nor how high the shear rate. However, for concentrated entangled polymer solutions, the magnitude of N2 becomes large at high shear rates. Therefore, in order to test the hypothesis that N2 can be used to induce multiple particle stream focusing behavior, we perform the systematic study of the effects of increasing carrier fluid polymer concentrations in a microchannel containing fluorescent particles. In a dilute polymer solution, multiple particle stream focusing is not observed, even at high shear rates and large dimensionless Weissenberg number values (Wi ≈ 30) at which the elastic first normal stress difference (N1) and the viscosity shear-thinning should be very large, while in a concentrated entangled polymer solution, we observe that particle streams focused upon the channel centerline bifurcate to form two symmetric off-channel particle streams at higher shear rates. This particle focusing behavior is different from previous multiple-stream focusing phenomena, and that we attribute to the influence of the second normal stress difference N2. This N2 induced multiple stream focusing phenomenon provides a different approach for manipulating the particle trajectory and separation in a microchannel.

Bio-mimetic synthetic cell hydrogel magnetometer.

We present a bio-inspired hydrogel magnetometer where the cell potential (V oc) between two hydrogels is used to measure an external magnetic field. Ferromagnetic particles located in the hydrogels move in response to the external field and change the V oc (sensitivity ~ 3.7 V T-1). As the field becomes larger than a critical field B c (~38 mT), these particles puncture the hydrogel boundary shorting out the concentration gradient region and abruptly reducing the V oc (sensitivity ~ 23.5 V T-1). In this regime, the V oc behaves similar to the neuron firing. In subsequent measurement cycles, the particles remain in punctured holes and the sensor behaviour is neuron-like with lower sensitivity (~20 V T-1). V oc also changes as a function of pressure (8 mV kPa-1) and temperature (2 mV K-1). After 4 h, the ionic concentration gradient diminishes in the device, and similar to biological cell fatigue, V oc decreases and can be recharged with many different techniques.

Remote Microwave and Field-Effect Sensing Techniques for Monitoring Hydrogel Sensor Response.

This paper presents two novel techniques for monitoring the response of smart hydrogels composed of synthetic organic materials that can be engineered to respond (swell or shrink, change conductivity and optical properties) to specific chemicals, biomolecules or external stimuli. The first technique uses microwaves both in contact and remote monitoring of the hydrogel as it responds to chemicals. This method is of great interest because it can be used to non-invasively monitor the response of subcutaneously implanted hydrogels to blood chemicals such as oxygen and glucose. The second technique uses a metal-oxide-hydrogel field-effect transistor (MOHFET) and its associated current-voltage characteristics to monitor the hydrogel's response to different chemicals. MOHFET can be easily integrated with on-board telemetry electronics for applications in implantable biosensors or it can be used as a transistor in an oscillator circuit where the oscillation frequency of the circuit depends on the analyte concentration.

Low-Cost Microfluidic Sensors with Smart Hydrogel Patterned Arrays Using Electronic Resistive Channel Sensing for Readout.

There is a strong commercial need for inexpensive point-of-use sensors for monitoring disease biomarkers or environmental contaminants in drinking water. Point-of-use sensors that employ smart polymer hydrogels as recognition elements can be tailored to detect almost any target analyte, but often suffer from long response times. Hence, we describe here a fabrication process that can be used to manufacture low-cost point-of-use hydrogel-based microfluidics sensors with short response times. In this process, mask-templated UV photopolymerization is used to produce arrays of smart hydrogel pillars inside sub-millimeter channels located upon microfluidics devices. When these pillars contact aqueous solutions containing a target analyte, they swell or shrink, thereby changing the resistance of the microfluidic channel to ionic current flow when a small bias voltage is applied to the system. Hence resistance measurements can be used to transduce hydrogel swelling changes into electrical signals. The only instrumentation required is a simple portable potentiostat that can be operated using a smartphone or a laptop, thus making the system suitable for point of use. Rapid hydrogel response rate is achieved by fabricating arrays of smart hydrogels that have large surface area-to-volume ratios.

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.

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.

Structural, mechanical and osmotic properties of injectable hyaluronan-based composite hydrogels.

The osmotic and scattering properties of hyaluronan-based composite hydrogels composed of stiff biopolymer chains (carboxymethylated thiolated hyaluronan (CMHA-S)) crosslinked by a flexible polymer (polyethylene glycol diacrylate (PEGDA)) are investigated and analyzed in terms of the scaling theory. The total pre-gel polymer weight concentration is varied between 0.5 wt.% and 3.2 wt.%, while the mole ratio between the reactive PEG chain ends and the thiolated HA moieties is changed between 0.15 and 1.0. The shear modulus G of the fully swollen gels exhibits a stronger dependence on pre-gel concentration than on the crosslink density. Osmotic deswelling measurements reveal that the osmotic mixing pressure depends on the weight ratio CMHA-S/PEGDA, and is practically unaffected by the pre-gel concentration. Small-angle neutron scattering observations indicate that the thermodynamic properties of these composite gels are governed by total polymer concentration, i.e., specific interactions between the two polymeric components do not play a significant role.

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.

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.