Smart hydrogels are a versatile class of materials that are attractive for biomedical sensor applications due to their potential biocompatibility and stimuli-responsiveness. However, the integration of these hydrogels into sensors requires development and engineering efforts to optimize the volume phase transition and time response for the respective sensing applications. This work presents an optical evaluation platform for investigating hydrogel swelling properties in a liquid environment with automated flow control. It employs hydrogel features integrated in microfluidic test strips which are easily interchangeable. The evaluation is carried out using an image sensor that records multiple miniaturized hydrogels in parallel. Overall performance is demonstrated by studying the swelling respones of two different hydrogel compositions (based on acrylamide: a polyampholytic glucose-responsive hydrogel as well as a hydrogel optimized for response to ionic strength and temperature) to various external stimuli, which include sodium chloride, temperature, and glucose as well as glucose spiked into serum and blood. The inclusion of relevant body fluids used in diagnostics potentially enables pathways for this sensing platform to be employed at the point-of-care setting.

Smart hydrogels hold great promise as sensing elements that can be tailored to respond to a wide array of biomarkers and can be integrated with different readout modalities. However, a major challenge with these sensors is response time, which depends on the hydrogel swelling behavior and is limited by diffusion. While geometrical miniaturization can accelerate response time, it often requires complex readout systems to detect volume changes, which is detrimental for use in point-of-need (PoN) applications. This study introduces a novel approach for hydrogel-based platforms that realizes important PoN requirements such as sensitivity, cost-effectiveness, instrument-free, and fast response time. The proposed sensing mechanism involves constraining a hydrogel strand at both ends and utilizing a visually observable buckling behavior instead of directly measuring a volume change. The sensing principle is validated by measuring glucose, an important biological analyte, and examines measurement repeatability, response time, sensitivity, and dynamic range. The performance is also demonstrated in blood and serum. The effects of design parameters such as strand length and diameter on sensor performance are also investigated. This new sensor offers a straightforward visual readout without requiring complex instrumentation, paving the way for more accessible and affordable PoN devices.

Stimulus-responsive hydrogels are a group of materials that are frequently investigated for their use as transducers in biomedical sensors due to their potential biocompatibility, wide range of available environmental properties to be measured and the established straightforward microfabrication approaches. However, the measurement of biomarkers, such as glucose, is often subject to long response times in the range of minutes to hours, which can be unfavourable for point-of-care applications. One way to significantly reduce these long response times is the force compensation measurement method, in which the time-consuming volume-phase transition (VPT) of the hydrogel is suppressed. An attractive way to implement this method is given by using a dual-responsive hydrogel that, in addition to its original intended stimulus also features a responsiveness to temperature changes. In this work, a dual-responsive hydrogel is presented that is intended for glucose measurement and is equipped with the additional temperature responsiveness for swelling suppression. The measurement range of the hydrogel covers the physiologically relevant level and compensation temperatures are within a biomedically favorable span of 20°C to 40°C. Its dynamic and static swelling properties are specifically tailored for the application in compensated hydrogel-based sensors, which makes it usable for improved glucose sensors and, thus, offers potential for shortening the response time of corresponding glucose measuring devices.

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.

Soft solids that swell with shifts in pressure, temperature and pH provide a way of detecting such changes in the fluid around the brain. The method could be used to determine other properties of fluids elsewhere in the body. Injectable hydrogels gauge changes in the brain.

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.

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.

Smart hydrogels are stimuli-responsive polymers which exhibit a volume-phase transition in response to external influences. This makes them promising candidates for sensing elements, especially in a biomedical context due to their easily achievable biocompatibility. The main challenge in harnessing the smart polymer’s potential for sensor applications lies in a reliable transduction of the swelling change into an electrical signal. A novel platform approach is based on a bending sensor where the smart hydrogel acts as an actuator on a thin film with embedded metal traces. Mechanical deformation due to the hydrogel volume change alters the traces’ electric impedance. However, besides deformation, the medium surrounding the sensor structure will also affect the impedance. For sensor design it is therefore crucial to understand the complex interdependencies between electric sensor properties, influences of the surrounding medium and mechanical deformation. Here, an electric circuit model is presented which considers all these contributions through a minimum number of lumped elements and is strictly based on physical considerations. By employing measured impedance spectra from an experimental sensor implementation subjected to different surrounding media and mechanical deformation, the validity of the simplified model is demonstrated. A detailed analysis and discussion give insights into the determination of the different model parameters and how external influences can clearly be attributed to specific circuit elements. This work provides a general approach for deducing minimalistic but strictly physics-based circuit models which can still adequately replicate the actual behavior of such types of impedance-based bending sensors.

Smart (stimuli-responsive) hydrogels constitute a material class suitable for transducers in sensing applications due to their volume-phase transition in response to a change in environmental parameters. In order to assess the viability of new hydrogel compositions for sensing, an easily applicable yet reliable characterization method for relevant static and dynamic properties of the gels, such as swelling and deswelling time constants, repeatability, stability as well as the relative swelling ratio, is crucial. Here we present such an easy-to-implement and affordable method based on the optical detection of the hydrogel's swelling state. We demonstrate the method's viability for characterization of various samples and discuss its advantages and limitations. Additionally, we fully describe the necessary experimental setup, software for automated data evaluation and corresponding proced-ures to allow interested researchers to implement the method in their own laboratories.

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.

The current field of sensor platforms is substantial, and ever more creative approaches are envisioned and realized. Herein, we showcase a new platform technology for continuous sensing that relies on the resonant absorption of ultrasound waves in a microfabricated array of smart hydrogel structures (see Figure 1).[1] Smart hydrogels are biocompatible and can be tailored to respond to different analytes. [2,3] These selective materials undergo a volume-phase transition in response to changing levels of biomarkers. In addition, smart hydrogels can be based on compositions that include poly(ethylene glycol), poly(methyl methacrylate), or hyaluronic acid to be designed to biodegrade. By employing smart hydrogels as resonator structures and probing them using ultrasound will provide an implantable sensor platform that is minimally invasive, non-destructive, and free of transcutaneous wires. This approach makes use of the fact that hydrogels can be molded into mechanical microresonators that are tuned to a specific ultrasound frequency. As they swell or contract in response to the presence or absence of the target analyte, their resonance frequency changes, leading to a shift in the ultrasound absorption spectrum. Measuring these changes allows for the reconstruction of the analyte concentration. In addition to that, tailoring the resonance frequency of the smart hydrogel resonator structures to different frequency ranges allows for multiplexing. We successfully demonstrate the use of this platform technology using glucose as a target metabolic marker in-vitro and in-vivo in rats (see Figure 2). Florian Solzbacher declares financial interest in Blackrock Microsystems LLC and Sentiomed, Inc. Jules Magda declares financial interest in Applied Biosensors LLC. [1] N. Farhoudi, H.-Y.L., J. Magda, F. Solzbacher and C.F. Reiche, A Biomedical Sensor Based on Resonant Absorption of Ultrasound Waves in Hydrogel-based Resonators. TechConnect Briefs 2019, 2019: p. 412. [2] Buenger, F. Topuz, and J. Groll, “Hydrogels in sensing applications,” Prog. Polym. Sci., vol. 37, no. 12, pp. 1678–1719, 2012. [3] A. Peppas, J. Z. Hilt, A. Khademhosseini, and R. Langer, “Hydrogels in biology and medicine:From molecular principles to bionanotechnology,” Adv. Mater., vol. 18, no. 11, pp. 1345–1360, Jun. 2006. Figure 1

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.

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.

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.

Many biomedical sensing concepts for continuous monitoring of analytes rely on implanting electronic components inside the body to operate, which raises issues about long-term biocompatibility. In recent reports, an implantable sensing modality was reported in which ultrasound absorption in smart hydrogel resonators at a particular probing frequency is used to track the changes in ionic strength and glucose concentration of an analyte solution. This sensing concept allows the implanted component to be free from electronics, with corresponding possible advantages with respect to biocompatibility and lifetime of the device. However, an unsuitable probing frequency can undermine the received signal's quality from the implants or even entirely cause a signal loss. Here we present our work on creating an ultrasound characterization system and using it to determine optimum probing frequencies for the hydrogel resonator structures within a given frequency window. Furthermore, we demonstrate that the signal amplitude depends on the probing frequency's location relative to the frequency response peaks at a fixed dynamic range for swelling of smart hydrogels.

Waxy crude oils are becoming increasingly important in worldwide oil production. Due to the existence of suspended wax crystals during shear flows, waxy crude oils usually exhibit large non-Newtonian shear viscosity values and thixotropic behaviors (time-dependent yield stress). Thus, accurate pipe-flow prediction models are needed in order to support pipeline oil transportation operation and design. Recent rheological studies have shown that the presheared waxy oil slurry below its wax appearance temperature exhibits a large shear stress overshoot during start-up after a short period time of static aging. To investigate the pipe flows of model waxy crude oils, a bench-scale flow loop (test section ID = 1.02 cm, length = 1.37 m) and a pilot-scale flow loop (test section ID = 2.67 cm, length = 3.81 m) were built suitable for studying the steady-state and transient flow behaviors. The temperatures and pressures across the entire test section were measured during the flow experiments. Model oils containing 7 and 10 wt % wax were studied. Steady-state pressures were obtained at a variety of flow rates. Overshoots in pressure were observed at the beginning of the start-up flow. The overshoot was attributed to the buildup of a wax gel structure during quiescent aging periods. A pipeline model that incorporates the isotropic-kinematic hardening rheology model is proposed. The parameters of this model were obtained by laboratory cone-plate rheology measurements. The cone-plate shear stress of the waxy model oil exhibits a relative minimum when plotted against the shear rate. The pressure drop profiles of steady-state and transient start-up flows were predicted by the developed pipe-flow model.

Smart hydrogel structures can be used as chemical sensing components to measure the changes in the environmental concentration of analytes of biomedical relevance. Sensing schemes using smart hydrogels rely on the transduction of the stimulated change of the hydrogels’ physical properties into a usable signal. Recently, we reported on such a sensing technique employing resonance absorption of ultrasound in smart hydrogel microresonator structures as well as in a hydrogel sheet using medical ultrasound imaging as the transduction method. However, the mold-based fabrication process limited the possible geometries of the hydrogel structures, which resulted in a constrained response time. In this publication, we present an improved fast and cost-efficient fabrication process to create arrays of free-standing stimuli-responsive hydrogel pillars that can be used to address this challenge along with first preliminary experimental results using these smart hydrogel structures for ionic strength 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.