Methods of ex vivo analysis of tissue status in vascularized composite allografts.

Vascularized composite allotransplantation can improve quality of life and restore functionality. However, the complex tissue composition of vascularized composite allografts (VCAs) presents unique clinical challenges that increase the likelihood of transplant rejection. Under prolonged static cold storage, highly damage-susceptible tissues such as muscle and nerve undergo irreversible degradation that may render allografts non-functional. Skin-containing VCA elicits an immunogenic response that increases the risk of recipient allograft rejection. The development of quantitative metrics to evaluate VCAs prior to and following transplantation are key to mitigating allograft rejection. Correspondingly, a broad range of bioanalytical methods have emerged to assess the progression of VCA rejection and characterize transplantation outcomes. To consolidate the current range of relevant technologies and expand on potential for development, methods to evaluate ex vivo VCA status are herein reviewed and comparatively assessed. The use of implantable physiological status monitoring biochips, non-invasive bioimpedance monitoring to assess edema, and deep learning algorithms to fuse disparate inputs to stratify VCAs are identified.

Electrospun electroconductive constructs of aligned fibers for cardiac tissue engineering.

Myocardial infarction remains the leading cause of death in the western world. Since the heart has limited regenerative capabilities, several cardiac tissue engineering (CTE) strategies have been proposed to repair the damaged myocardium. A novel electrospun construct with aligned and electroconductive fibers combining gelatin, poly(lactic-co-glycolic) acid and polypyrrole that may serve as a cardiac patch is presented. Constructs were characterized for fiber alignment, surface wettability, shrinkage and swelling behavior, porosity, degradation rate, mechanical properties, and electrical properties. Cell-biomaterial interactions were studied using three different types of cells, Neonatal Rat Ventricular Myocytes (NRVM), human lung fibroblasts (MRC-5) and induced pluripotent stem cells (iPSCs). All cell types showed good viability and unique organization on construct surfaces depending on their phenotype. Finally, we assessed the maturation status of NRVMs after 14 days by confocal images and qRT-PCR. Overall evidence supports a proof-of-concept that this novel biomaterial construct could be a good candidate patch for CTE applications.

Polyamorphism in vapor-deposited 2-methyltetrahydrofuran: A broadband dielectric relaxation study.

Depositing a simple organic molecular glass-former 2-methyltetrahydrofuran (MTHF) onto an interdigitated electrode device via physical vapor deposition gives rise to an unexpected variety of states, as revealed by dielectric spectroscopy. Different preparation parameters, such as deposition temperature, deposition rate, and annealing conditions, lead, on the one hand, to an ultrastable glass and, on the other hand, to a continuum of newfound further states. Deposition below the glass transition temperature of MTHF leads to loss profiles with shape parameters and peak frequencies that differ from those of the known bulk MTHF. These loss spectra also reveal an additional process with Arrhenius-like temperature dependence, which can be more than four decades slower than the main structural relaxation peak. At a given temperature, the time constants of MTHF deposited between 120 K and 127 K span a range of more than three decades and their temperature dependencies change from strong to fragile behavior. This polyamorphism involves at least three distinct states, each persisting for a duration many orders of magnitude above the dielectric relaxation time. These results represent a significant expansion of a previous dielectric study on vapor deposited MTHF [B. Riechers et al., J. Chem. Phys. 150, 214502 (2019)]. Plastic crystal states and the effects of weak hydrogen bonding are discussed as structural features that could explain these unusual states.

Toward a hemorrhagic trauma severity score: fusing five physiological biomarkers.

BACKGROUND: To introduce the Hemorrhage Intensive Severity and Survivability (HISS) score, based on the fusion of multi-biomarker data; glucose, lactate, pH, potassium, and oxygen tension, to serve as a patient-specific attribute in hemorrhagic trauma. MATERIALS AND METHODS: One hundred instances of Sensible Fictitious Rationalized Patient (SFRP) data were synthetically generated and the HISS score assigned by five clinically active physician experts (100 [5]). The HISS score stratifies the criticality of the trauma patient as; low(0), guarded(1), elevated(2), high(3) and severe(4). Standard classifier algorithms; linear support vector machine (SVM-L), multi-class ensemble bagged decision tree (EBDT), artificial neural network with bayesian regularization (ANN:BR) and possibility rule-based using function approximation (PRBF) were evaluated for their potential to similarly classify and predict a HISS score. RESULTS: SVM-L, EBDT, ANN:BR and PRBF generated score predictions with testing accuracies (majority vote) corresponding to 0.91 ± 0.06, 0.93 ± 0.04, 0.92 ± 0.07, and 0.92 ± 0.03, respectively, with no statistically significant difference (p > 0.05). Targeted accuracies of 0.99 and 0.999 could be achieved with SFRP data size and clinical expert scores of 147[7](0.99) and 154[9](0.999), respectively. CONCLUSIONS: The predictions of the data-driven model in conjunction with an adjunct multi-analyte biosensor intended for point-of-care continual monitoring of trauma patients, can aid in patient stratification and triage decision-making.

Nanobiosensing with graphene and carbon quantum dots: Recent advances.

Graphene and carbon quantum dots (GQDs and CQDs) are relatively new nanomaterials that have demonstrated impact in multiple different fields thanks to their unique quantum properties and excellent biocompatibility. Biosensing, analyte detection and monitoring wherein a key feature is coupled molecular recognition and signal transduction, is one such field that is being greatly advanced by the use of GQDs and CQDs. In this review, recent progress on the development of biotransducers and biosensors enabled by the creative use of GQDs and CQDs is reviewed, with special emphasis on how these materials specifically interface with biomolecules to improve overall analyte detection. This review also introduces nano-enabled biotransducers and different biosensing configurations and strategies, as well as highlights key properties of GQDs and CQDs that are pertinent to functional biotransducer design. Following relevant introductory material, the literature is surveyed with emphasis on work performed over the last 5 years. General comments and suggestions to advance the direction and potential of the field are included throughout the review. The strategic purpose is to inspire and guide future investigations into biosensor design for quality and safety, as well as serve as a primer for developing GQD- and CQD-based biosensors.

Site of Tagging Influences the Ochratoxin Recognition by Peptide NFO4: A Molecular Dynamics Study.

Molecular recognition by synthetic peptides is growing in importance in the design of biosensing elements used in the detection and monitoring of a wide variety of hapten bioanlaytes. Conferring specificity via bioimmobilization and subsequent recovery and purification of such sensing elements are aided by the use of affinity tags. However, the tag and its site of placement can potentially compromise the hapten recognition capabilities of the peptide, necessitating a detailed experimental characterization and optimization of the tagged molecular recognition entity. The objective of this study was to assess the impact of site-specific tags on a native peptide's fold and hapten recognition capabilities using an advanced molecular dynamics (MD) simulation approach involving bias-exchange metadynamics and Markov State Models. The in-solution binding preferences of affinity tagged NFO4 (VYMNRKYYKCCK) to chlorinated (OTA) and non-chlorinated (OTB) analogues of ochratoxin were evaluated by appending hexa-histidine tags (6× His-tag) to the peptide's N-terminus (NterNFO4) or C-terminus (CterNFO4), respectively. The untagged NFO4 (NFO4), previously shown to bind with high affinity and selectivity to OTA, served as the control. Results indicate that the addition of site-specific 6× His-tags altered the peptide's native fold and the ochratoxin binding mechanism, with the influence of site-specific affinity tags being most evident on the peptide's interaction with OTA. The tags at the N-terminus of NFO4 preserved the native fold and actively contributed to the nonbonded interactions with OTA. In contrast, the tags at the C-terminus of NFO4 altered the native fold and were agnostic in its nonbonded interactions with OTA. The tags also increased the penalty associated with solvating the peptide-OTA complex. Interestingly, the tags did not significantly influence the nonbonded interactions or the penalty associated with solvating the peptide-OTB complex. Overall, the combined contributions of nonbonded interaction and solvation penalty were responsible for the retention of the native hapten recognition capabilities in NterNFO4 and compromised native recognition capabilities in CterNFO4. Advanced MD approaches can thus provide structural and energetic insights critical to evaluate the impact of site-specific tags and may aid in the selection and optimization of the binding preferences of a specific biosensing element.

Adherence-Promoting Design Features in Pediatric Neurostimulators for ADHD Patients.

The emergence of remote health monitoring and increased at-home care emphasizes the importance of patient adherence outside the clinical setting. This is particularly pertinent in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients, as the population inherently has difficulty remembering and initiating treatment tasks. Neurostimulation is an emerging treatment modality for pediatric ADHD and requires strict adherence to a treatment regimen to be followed in an at-home setting. Thus, to achieve the desired therapeutic effect, careful attention must be paid to design features that can passively promote and effectively monitor therapeutic adherence. This work describes instrumentation designed to support a clinical trial protocol that tests whether choice of color, or color itself, can statistically significantly increase adherence rates in pediatric ADHD patients in an extraclinical environment. This is made possible through the development and application of an internet-of-things approach in a remote adherence monitoring technology that can be implemented in forthcoming neurostimulation devices for pediatric patient use. This instrumentation requires minimal input from the user, is durable and resistant to physical damage, and provides accurate adherence data to parents and physicians, increasing assurance that neurostimulation devices are effective for at-home care.

Monitoring systems and quantitative measurement of biomolecules for the management of trauma.

Continued high morbidity and complications due to trauma related hemorrhage underscores the fact that our understanding of the detailed molecular events of trauma are inadequate to bring life-saving changes to practice. The current state of efficacy and advances in biomedical microdevice technology for trauma diagnostics concerning hemorrhage and hemorrhagic shock was considered with respect to vital signs and metabolic biomarkers. Tachycardia and hypotension are markers of hemorrhagic shock in decompensated trauma patients. Base deficit has been predicative of injury severity at hospital admission. Tissue oxygen saturation has been predicative of onset of multiple organ dysfunction syndrome. Blood potassium levels increase with onset of hemorrhagic shock. Lactate is a surrogate for tissue hypoxia and its clearance predicts mortality. Triage glucose measurements have been shown to be specific in predicting major injuries. No vital sign has yet to be proven effective as an independent predictor of trauma severity. Point of care (POC) devices allow for rapid results, easy sample preparation and processing, small sample volumes, small footprint, multifunctional analysis, and low cost. Advances in the field of in-vivo biosensors has provided a much needed platform by which trauma related metabolites can be monitored easily, rapidly and continuously. Multi-analyte monitoring biosensors have the potential to explore areas still undiscovered in the realm of trauma physiology.

Silicon carbide: a versatile material for biosensor applications.

Silicon carbide (SiC) has been around for more than 100 years as an industrial material and has found wide and varied applications because of its unique electrical and thermal properties. In recent years there has been increased attention to SiC as a viable material for biomedical applications. Of particular interest in this review is its potential for application as a biotransducer in biosensors. Among these applications are those where SiC is used as a substrate material, taking advantage of its surface chemical, tribological and electrical properties. In addition, its potential for integration as system on a chip and those applications where SiC is used as an active material make it a suitable substrate for micro-device fabrication. This review highlights the critical properties of SiC for application as a biosensor and reviews recent work reported on using SiC as an active or passive material in biotransducers and biosensors.

Supramolecular glucose oxidase-SWNT conjugates formed by ultrasonication: effect of tube length, functionalization and processing time.

BACKGROUND: Generation-3 (Gen-3) biosensors and advanced enzyme biofuel cells will benefit from direct electron transfer to oxidoreductases facilitated by single-walled carbon nanotubes (SWNTs). METHODS: Supramolecular conjugates of SWNT-glucose oxidase (GOx-SWNT) were produced via ultrasonic processing. Using a Plackett-Burman experimental design to investigate the process of tip ultrasonication (23 kHz), conjugate formation was investigated as a function of ultrasonication times (0, 5, 60 min) and functionalized SWNTs of various tube lengths (SWNT-X-L), (X = -OH or -COOH and L = 3.0 µm, 7.5 µm). RESULTS: Enzyme activity (KM, kcat, kcat/KM, vmax and n (the Hill parameter)) of pGOx (pristine), sGOx (sonicated) and GOx-SWNT-X-L revealed that sonication of any duration increased both KM and kcat of GOx but did not change kcat/KM. Functionalized tubes had the most dramatic effect, reducing both KM and kcat and reducing kcat/KM. UV-vis spectra over the range of 300 to 550 nm of native enzyme-bound FAD (λmax at 381 and 452 nm) or the blue-shifted solvated FAD of the denatured enzyme (λmax at 377 and 448 nm) revealed that ultrasonication up to 60 minutes had no influence on spectral characteristics of FAD but that the longer SWNTs caused some partial denaturation leading to egress of FAD. Circular dichroism spectral analysis of the 2° structure showed that sonication of any duration caused enrichment in the α-helical content at the sacrifice of the unordered sequences in GOx while the presence of SWNTs, regardless of length and/or functionality, reduced the ß-sheet content of pristine GOx. Surface profiling by white light interferometry revealed that ultrasonication produced some aggregation of GOx and that GOx effectively debundled the SWNT. CONCLUSIONS: Supramolecular conjugates formed from shorter, -OH functionalized SWNTs using longer sonication times (60 min) gave the most favored combination for forming bioactive conjugates.

Electrically stimulated gene expression under exogenously applied electric fields.

Introduction: Electrical stimulation, the application of an electric field to cells and tissues grown in culture to accelerate growth and tight junction formation among endothelial cells, could be impactful in cardiovascular tissue engineering, allotransplantation, and wound healing. Methods: Using Electrical Cell Stimulation And Recording Apparatus (ECSARA), the exploration of the stimulatory influences of electric fields of different magnitude and frequencies on growth and proliferation, trans endothelial electrical resistance (TEER) and gene expression of human endothelia cells (HUVECs) were explored. Results: Within the range of endogenous electrical pulses studied, frequency was found to be more significant (p = 0.05) than voltage in influencing HUVEC gene expression. Localization of Yes Associated Protein (YAP) and expression of CD-144 are shown to be consistent with temporal manifestations of TEER. Discussion: This work introduces the field of electromics, the study of cellular gene expression profiles and their implications under the influence of exogenously applied electric fields. Homology of electrobiology and mechanobiology suggests use of such exogenous cues in tissue and regenerative engineering.

Real-Time Monitoring Using Multiplexed Multi-Electrode Bioelectrical Impedance Spectroscopy for the Stratification of Vascularized Composite Allografts: A Perspective on Predictive Analytics.

Vascularized composite allotransplantation addresses injuries to complex anatomical structures such as the face, hand, and abdominal wall. Prolonged static cold storage of vascularized composite allografts (VCA) incurs damage and imposes transportation limits to their viability and availability. Tissue ischemia, the major clinical indication, is strongly correlated with negative transplantation outcomes. Machine perfusion and normothermia can extend preservation times. This perspective introduces multiplexed multi-electrode bioimpedance spectroscopy (MMBIS), an established bioanalytical method to quantify the interaction of the electrical current with tissue components, capable of measuring tissue edema, as a quantitative, noninvasive, real-time, continuous monitoring technique to provide crucially needed assessment of graft preservation efficacy and viability. MMBIS must be developed, and appropriate models explored to address the highly complex multi-tissue structures and time-temperature changes of VCA. Combined with artificial intelligence (AI), MMBIS can serve to stratify allografts for improvement in transplantation outcomes.

Biomimetic hydrogels gate transport of calcium ions across cell culture inserts.

Control of the in vitro spatiotemporal availability of calcium ions is one means by which the microenvironments of hematopoietic stem cells grown in culture may be reproduced. The effects of cross-linking density on the diffusivity of calcium ions through cell culture compatible poly(2-hydroxyethyl methacrylate) [poly(HEMA)]-based bioactive hydrogels possessing 1.0 mol% 2-methacryloyloxyethyl phosphorylcholine (MPC), 5 mol% N,N-(dimethylamino)ethylmethacrylate (DMAEMA) and ca. 17 mol% n-butyl acrylate (n-BA) have been investigated to determine if varying cross-link density is a viable approach to controlling transport of calcium across hydrogel membranes. Cross-linking density was varied by changing the composition of cross-linker, tetraethyleneglycol diacrylate (TEGDA). The hydrogel membranes were formed by sandwich casting onto the external surface of track-etched polycarbonate membranes (T = 10 µm, φ = 0.4 µm pores) of cell culture inserts, polymerized in place by UV light irradiation and immersed in buffered (0.025 HEPES, pH 7.4) 0.10 M calcium chloride solution. The transport of calcium ions across the hydrogel membrane was monitored using a calcium ion selective electrode set within the insert. Degree of hydration (21.6 ± 1.0%) and void fraction were found to be constant across all cross-linking densities. Diffusion coefficients, determined using time-lag analysis, were shown to be strongly dependent on and to exponentially decrease with increasing cross-linking density. Compared to that found in buffer (2.0-2.5 × 10⁻6 cm²/s), diffusion coefficients ranged from 1.40 × 10⁻6 cm²/s to 1.80 × 10⁻7 cm²/s and tortuosity values ranged from 1.7 to 10.0 for the 1 and 12 mol% TEGDA cross-linked hydrogels respectively. Changes in tortuosity arising from variations in cross-link density were found to be the primary modality for controlling diffusivity through novel n-BA containing poly(HEMA)-based bioactive hydrogels.

Fully integrated biochip platforms for advanced healthcare.

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications.

Bioelectrical Impedance Spectroscopy for Monitoring Mammalian Cells and Tissues under Different Frequency Domains: A Review.

Bioelectrical impedance analysis and bioelectrical impedance spectroscopy (BIA/BIS) of tissues reveal important information on molecular composition and physical structure that is useful in diagnostics and prognostics. The heterogeneity in structural elements of cells, tissues, organs, and the whole human body, the variability in molecular composition arising from the dynamics of biochemical reactions, and the contributions of inherently electroresponsive components, such as ions, proteins, and polarized membranes, have rendered bioimpedance challenging to interpret but also a powerful evaluation and monitoring technique in biomedicine. BIA/BIS has thus become the basis for a wide range of diagnostic and monitoring systems such as plethysmography and tomography. The use of BIA/BIS arises from (i) being a noninvasive and safe measurement modality, (ii) its ease of miniaturization, and (iii) multiple technological formats for its biomedical implementation. Considering the dependency of the absolute and relative values of impedance on frequency, and the uniqueness of the origins of the α-, ß-, δ-, and γ-dispersions, this targeted review discusses biological events and underlying principles that are employed to analyze the impedance data based on the frequency range. The emergence of BIA/BIS in wearable devices and its relevance to the Internet of Medical Things (IoMT) are introduced and discussed.

Nanoengineered Ink for Designing 3D Printable Flexible Bioelectronics.

Flexible electronics require elastomeric and conductive biointerfaces with native tissue-like mechanical properties. The conventional approaches to engineer such a biointerface often utilize conductive nanomaterials in combination with polymeric hydrogels that are cross-linked using toxic photoinitiators. Moreover, these systems frequently demonstrate poor biocompatibility and face trade-offs between conductivity and mechanical stiffness under physiological conditions. To address these challenges, we developed a class of shear-thinning hydrogels as biomaterial inks for 3D printing flexible bioelectronics. These hydrogels are engineered through a facile vacancy-driven gelation of MoS2 nanoassemblies with naturally derived polymer-thiolated gelatin. Due to shear-thinning properties, these nanoengineered hydrogels can be printed into complex shapes that can respond to mechanical deformation. The chemically cross-linked nanoengineered hydrogels demonstrate a 20-fold rise in compressive moduli and can withstand up to 80% strain without permanent deformation, meeting human anatomical flexibility. The nanoengineered network exhibits high conductivity, compressive modulus, pseudocapacitance, and biocompatibility. The 3D-printed cross-linked structure demonstrates excellent strain sensitivity and can be used as wearable electronics to detect various motion dynamics. Overall, the results suggest that these nanoengineered hydrogels offer improved mechanical, electronic, and biological characteristics for various emerging biomedical applications including 3D-printed flexible biosensors, actuators, optoelectronics, and therapeutic delivery devices.

Design considerations in the use of interdigitated microsensor electrode arrays (IMEs) for impedimetric characterization of biomimetic hydrogels.

Microlithographically fabricated interdigitated microsensor electrodes (IMEs) were cleaned, surface activated, chemically functionalized (amine) and derivatized with an Acrloyl-PEG-NHS to receive a spun-applied monomer cocktail of UV polymerizable monomer. IMEs were 2050.5, 1550.5, 1050.5 and 0550.5 possessing lines and spaces that were 20, 15, 10, and 5 µm respectively; 5 mm line lengths and were 50 lines on each opposing bus. Bioactive hydrogels were synthesized from spun-applied and UV-crosslinked tetraethyleneglycol diacrylate (TEGDA) (crosslinker), 2-hydroxyethylmethacrylate (HEMA), polyethyleneglycol(200) monomethacrylate (PEGMA), N-[tris(hydroxymethyl)methyl]-acrylamide (HMMA) and poly(HEMA) (MW 60,000) (viscosity modifier) and 2,2-dimethoxy-2-phenylacetophenone (DMPA) (photoinitiator) to produce a 5 µm thick p(HEMA-co-PEGMA-co-HMMA) hydrogel membrane on the IMEs. Unmodified and hydrogel coated IMEs where characterized by AC electrical impedance spectroscopy using 50 mV p-t-p over the frequency range from 10 Hz to 100 kHz in aqueous PBS 7.4 buffer and in buffer containing 50 mM [Fe(CN)(6)](3-/4- ) solution at RT. Impedimetric responses were found to scale with the device geometric parameters. Equivalent circuit modeling revealed deviations from ideality at lower device dimensions suggesting an implication of the substrate surface charge on the double layer capacitance of the electrodes. Diffusion coefficients derived from the Warburg component are in accord with literature values.

An implantable biochip to influence patient outcomes following trauma-induced hemorrhage.

Following hemorrhage-causing injury, lactate levels rise and correlate with the severity of injury and are a surrogate of oxygen debt. Posttraumatic injury also includes hyperglycemia, with continuously elevated glucose levels leading to extensive tissue damage, septicemia, and multiple organ dysfunction syndrome. A temporary, implantable, integrated glucose and lactate biosensor and communications biochip for physiological status monitoring during hemorrhage and for intensive care unit stays has been developed. The dual responsive, amperometric biotransducer uses the microdisc electrode array format upon which were separately immobilized glucose oxidase and lactate oxidase within biorecognition layers, 1.0-5.0 µm thick, of 3 mol% tetraethyleneglycol diacrylate cross-linked p(HEMA-co-PEGMA-co-HMMA-co-SPA)-p(Py-co-PyBA) electroconductive hydrogels. The device was then coated with a bioactive hydrogel layer containing phosphoryl choline and polyethylene glycol pendant moieties [p(HEMA-co-PEGMA-co-HMMA-co-MPC)] for indwelling biocompatibility. In vitro cell proliferation and viability studies confirmed both polymers to be non-cytotoxic; however, PPy-based electroconductive hydrogels showed greater RMS 13 and PC12 proliferation compared to controls. The glucose and lactate biotransducers exhibited linear dynamic ranges of 0.10-13.0 mM glucose and 1.0-7.0 mM and response times (t(95)) of 50 and 35-40 s, respectively. Operational stability gave 80% of the initial biosensor response after 5 days of continuous operation at 37 °C. Preliminary in vivo studies in a Sprague-Dawley hemorrhage model showed tissue lactate levels to rise more rapidly than systematic lactate. The potential for an implantable biochip that supports telemetric reporting of intramuscular lactate and glucose levels allows the refinement of resuscitation approaches for civilian and combat trauma victims.

On the intersection of molecular bioelectronics and biosensors: 20 Years of C3B.

Formed in 2000 at Virginia Commonwealth University, the Center for Bioelectronics, Biosensors and Biochips (C3B®) has subsequently been located at Clemson University and at Texas A&M University. Established as an industry-university collaborative center of excellence, the C3B has contributed new knowledge and technology in the areas of i) molecular bioelectronics, ii) responsive polymers, iii) multiplexed biosensor systems, and iv) bioelectronic biosensors. Noteworthy contributions in these areas include i) being the first to report direct electron transfer of oxidoreductase enzymes enabled by single walled carbon nanotubes and colloidal clays, ii) the molecular level integration of inherently conductive polymers with bioactive hydrogels using bi-functional monomers such as poly(pyrrole-co-3-pyrrolylbutyrate-conj-aminoethylmethacrylate) [PyBA-conj-AEMA] and 3-(1-ethyl methacryloylate)aniline to yield hetero-ladder electroconductive hydrogels, iii) the development of a multi-analyte physiological status monitoring biochip, and iv) the development of a bioanalytical Wien-bridge oscillator for the fused measurement to lactate and glucose. The present review takes a critical look of these contributions over the past 20 years and offers some perspective on the future of bioelectronics-based biosensors and systems. Particular attention is given to multiplexed biosensor systems and data fusion for rapid decision making.

Understanding ADHD: Toward an Innovative Therapeutic Intervention.

Attention deficit hyperactivity disorder (ADHD) is a pervasive condition affecting persons across all age groups, although it is primarily diagnosed in children. This neurological condition affects behavior, learning, and social adjustment and requires specific symptomatic criteria to be fulfilled for diagnosis. ADHD may be treated with a combination of psychological or psychiatric therapeutic interventions, but it often goes unattended. People with ADHD face societal bias challenges that impact how they manage the disorder and how they view themselves. This paper summarizes the present state of understanding of this disorder, with particular attention to early diagnosis and innovative therapeutic intervention. Contemporary understanding of the mind-brain duality allows for innovative therapeutic interventions based on neurological stimulation. This paper introduces the concept of neurostimulation as a therapeutic intervention for ADHD and poses the question of the relationship between patient adherence to self-administered therapy and the aesthetic design features of the neurostimulation device. By fabricating devices that go beyond safety and efficacy to embrace the aesthetic preferences of the patient, it is proposed that there will be improvements in patient adherence to a device intended to address ADHD.