Wireless Battery-free and Fully Implantable Organ Interfaces.

Advances in soft materials, miniaturized electronics, sensors, stimulators, radios, and battery-free power supplies are resulting in a new generation of fully implantable organ interfaces that leverage volumetric reduction and soft mechanics by eliminating electrochemical power storage. This device class offers the ability to provide high-fidelity readouts of physiological processes, enables stimulation, and allows control over organs to realize new therapeutic and diagnostic paradigms. Driven by seamless integration with connected infrastructure, these devices enable personalized digital medicine. Key to advances are carefully designed material, electrophysical, electrochemical, and electromagnetic systems that form implantables with mechanical properties closely matched to the target organ to deliver functionality that supports high-fidelity sensors and stimulators. The elimination of electrochemical power supplies enables control over device operation, anywhere from acute, to lifetimes matching the target subject with physical dimensions that supports imperceptible operation. This review provides a comprehensive overview of the basic building blocks of battery-free organ interfaces and related topics such as implantation, delivery, sterilization, and user acceptance. State of the art examples categorized by organ system and an outlook of interconnection and advanced strategies for computation leveraging the consistent power influx to elevate functionality of this device class over current battery-powered strategies is highlighted.

Biosymbiotic platform for chronic long-range monitoring of biosignals in limited resource settings.

Remote patient monitoring is a critical component of digital medicine, and the COVID-19 pandemic has further highlighted its importance. Wearable sensors aimed at noninvasive extraction and transmission of high-fidelity physiological data provide an avenue toward at-home diagnostics and therapeutics; however, the infrastructure requirements for such devices limit their use to areas with well-established connectivity. This accentuates the socioeconomic and geopolitical gap in digital health technology and points toward a need to provide access in areas that have limited resources. Low-power wide area network (LPWAN) protocols, such as LoRa, may provide an avenue toward connectivity in these settings; however, there has been limited work on realizing wearable devices with this functionality because of power and electromagnetic constraints. In this work, we introduce wearables with electromagnetic, electronic, and mechanical features provided by a biosymbiotic platform to realize high-fidelity biosignals transmission of 15 miles without the need for satellite infrastructure. The platform implements wireless power transfer for interaction-free recharging, enabling long-term and uninterrupted use over weeks without the need for the user to interact with the devices. This work presents demonstration of a continuously wearable device with this long-range capability that has the potential to serve resource-constrained and remote areas, providing equitable access to digital health.

Biosymbiotic haptic feedback - Sustained long term human machine interfaces.

Haptic technology permeates diverse fields and is receiving renewed attention for VR and AR applications. Advances in flexible electronics, facilitate the integration of haptic technologies into soft wearable systems, however, because of small footprint requirements face challenges of operational time requiring either large batteries, wired connections or frequent recharge, restricting the utility of haptic devices to short-duration tasks or low duty cycles, prohibiting continuously assisting applications. Currently many chronic applications are not investigated because of this technological gap. Here, we address wireless power and operation challenges with a biosymbiotic approach enabling continuous operation without user intervention, facilitated by wireless power transfer, eliminating the need for large batteries, and offering long-term haptic feedback without adhesive attachment to the body. These capabilities enable haptic feedback for robotic surgery training and posture correction over weeks of use with neural net computation. The demonstrations showcase that this device class expands use beyond conventional brick and strap or epidermally attached devices enabling new fields of use for imperceptible therapeutic and assistive haptic technologies supporting care and disease management.

Rapid nanocatalytic reaction using antibody-conjugated gold nanoparticles for simple and sensitive detection of parathyroid hormone.

Biomolecule-conjugated metal nanoparticles (NPs) have been primarily used as colorimetric labels in affinity-based bioassays for point-of-care testing. A facile electrochemical detection scheme using a rapid nanocatalytic reaction of a metal NP label is required to achieve more quantitative and sensitive point-of-care testing. Moreover, all the involved components should be stable in their dried form and solution. This study developed a stable component set that allows for rapid and simple nanocatalytic reactions combined with electrochemical detection and applied it for the sensitive detection of parathyroid hormone (PTH). The component set consists of an indium-tin oxide (ITO) electrode, ferrocenemethanol (FcMeOH), antibody-conjugated Au NPs, and ammonia borane (AB). Despite being a strong reducing agent, AB is selected because it is stable in its dried form and solution. The slow direct reaction between FcMeOH+ and AB provides a low electrochemical background, and the rapid nanocatalytic reaction allows for a high electrochemical signal. Under optimal conditions, PTH could be quantified in a wide range of concentrations in artificial serum, with a detection limit of ∼0.5 pg/mL. Clinical validation of the developed PTH immunosensor using real serum samples indicates that this novel electrochemical detection scheme is promising for quantitative and sensitive immunoassays for point-of-care testing.

Dicarboxylate-containing and fully substituted ferrocene with rapid dissolvability, high solubility, good stability, and moderate formal potential for mediated electrochemical detection.

An electron mediator with rapid dissolvability and high solubility in aqueous electrolyte solutions is essential for point-of-care testing based on mediated electrochemical detection. However, most ferrocenyl (Fc) compounds have slow dissolvability and poor solubility owing to high hydrophobicity of the Fc backbone. Moreover, many Fc compounds have poor stability and nonoptimal formal potential (). Herein, we present an Fc compound, Fc8m2c, which exhibits rapid dissolvability, high solubility, good stability, and moderate along with its high electron-mediation rate. The of Fc8m2c (0.17 V vs. Ag/AgCl) is tuned by two electron-withdrawing acyl substituents and eight electron-donating methyl substituents. Two pendant carboxylate groups of Fc8m2c allow for rapid dissolvability and high solubility (0.63 M in water), whereas full substitution in its two cyclopentadienyl ligands facilitates good chemical stability against decomposition in the presence of dissolved O2 and ambient light. A moderate enables the application of a potential of 0.07 V at which electrochemical background currents are low and also contributes toward resisting the decomposition of both Fc8m2c and Fc8m2c+. Fc8m2c provides a high electron-mediation rate constant (2.4 × 106 M-1 s-1) in glucose detection using glucose dehydrogenase. When Fc8m2c is applied to a glucose sensor, the calculated detection limit is ∼0.1 mM with a measurement period of 5 s. Considering that the normal concentration of glucose in serum is between 3.9 and 6.6 mM, the detection limit is sufficiently low. These results show that Fc8m2c is an excellent electron-mediator candidate for sensitive and rapid glucose detection.

Simple and fast Ag deposition method using a redox enzyme label and quinone substrate for the sensitive electrochemical detection of thyroid-stimulating hormone.

Enzyme-induced seedless Ag deposition is useful for selective Ag deposition and subsequent electrochemical Ag oxidation; however, a washing step is required after the deposition and before the electrochemical oxidation as the enzyme substrate can be oxidized during the electrochemical oxidation. Here, we report a fast Ag deposition method using a redox enzyme and quinone substrate that does not require a washing step. We found that the quinone substrate is reduced by a redox enzyme label, which is later oxidized to its original form via the reduction of Ag+ to Ag. Moreover, the quinone substrate is not electrochemically oxidized during the electrochemical Ag oxidation. We selected one diaphorase and 1,4-naphthoquinone from among seven redox enzymes (four diaphorases and three glucose-oxidizing enzymes) and six quinones, respectively. We applied this Ag deposition method for the detection of thyroid-stimulating hormone (TSH) over a dynamic range from 100 fg/mL to 100 ng/mL and found that TSH could be detected at concentrations as low as approximately 100 fg/mL in artificial serum. Therefore, the Ag deposition strategy developed in this study exhibits promising potential for ultrasensitive clinical applications.

Di(Thioether Sulfonate)-Substituted Quinolinedione as a Rapidly Dissoluble and Stable Electron Mediator and Its Application in Sensitive Biosensors.

The commonly required properties of diffusive electron mediators for point-of-care testing are rapid dissolubility, high stability, and moderate formal potential in aqueous solutions. Inspired by nature, various quinone-containing electron mediators have been developed; however, satisfying all these requirements remains a challenge. Herein, a strategic design toward quinones incorporating sulfonated thioether and nitrogen-containing heteroarene moieties as solubilizing, stabilizing, and formal potential-modulating groups is reported. A systematic investigation reveals that di(thioether sulfonate)-substituted quinoline-1,4-dione (QLS) and quinoxaline-1,4-dione (QXS) display water solubilities of ≈1 m and are rapidly dissoluble. By finely balancing the electron-donating effect of the thioethers and the electron-withdrawing effect of the nitrogen atom, formal potentials suitable for electrochemical biosensors are achieved with QLS and QXS (-0.15 and -0.09 V vs Ag/AgCl, respectively, at pH 7.4). QLS is stable for >1 d in PBS (pH 7.4) and for 1 h in tris buffer (pH 9.0), which is sufficient for point-of-care testing. Furthermore, QLS, with its high electron mediation ability, is successfully used in biosensors for sensitive detection of glucose and parathyroid hormone, demonstrating detection limits of ≈0.3 × 10-3 m and ≈2 pg mL-1 , respectively. This strategy produces organic electron mediators exhibiting rapid dissolution and high stability, and will find broad application beyond quinone-based biosensors.

Electrochemical immunoassay based on choline oxidase-peroxidase enzymatic cascade.

Horseradish peroxidase (HRP)-based electrochemical immunoassays are considered promising techniques for point-of-care clinical diagnostics, but the necessary addition of unstable H2O2 in the enzymatic system may hinder their practical application. Although glucose oxidase (GOx) has been widely explored for in situ generation of H2O2 in HRP-based immunoassay, the GOx-catalyzed reduction of oxidized peroxidase substrate may limit the immunosensing performance. Here, we report a sensitive electrochemical immunosensor based on a choline oxidase (ChOx)-HRP cascade reaction. In this design, ChOx catalyzes the oxidation of choline, during which H2O2 is generated in situ and thus oxidizes acetaminophen (APAP) in the presence of HRP. The electrochemical behavior of APAP in the ChOx-HRP cascade was compared with that of the commonly used GOx-HRP cascade, which confirmed that ChOx could be a superior preceding enzyme for sensitive immunoassay based on the bienzymatic cascade. The developed ChOx-HRP cascade was also further explored for a sandwich-type electrochemical immunoassay of parathyroid hormone in artificial and clinical serum. The calculated detection limit was ~3 pg/mL, indicating that the ChOx-HRP cascade is especially promising for highly sensitive electrochemical immunoassays when APAP is used as the peroxidase substrate.

Boosting electrochemical immunosensing performance by employing acetaminophen as a peroxidase substrate.

In horseradish peroxidase (HRP)-based electrochemical immunosensing, an appropriate HRP substrate needs to be chosen to obtain a high electrochemical signal-to-background ratio. This is limited by the unwanted electrochemical reduction of H2O2, oxidation of the substrate, and the slow electrochemical reduction of the product. Herein, we report acetaminophen (AMP) as a new HRP substrate that allows for highly sensitive immunosensing. Electrochemical behavior and immunosensing performance using AMP are compared with those using the most popular HRP substrate, hydroquinone (HQ). To maintain a high electrocatalytic activity even at an electrode modified with an immunosensing layer, an indium tin oxide electrode partially modified with reduced graphene oxide is employed. AMP allows for a higher signal-to-background ratio than HQ, because the formal potential of AMP is 0.28 V higher than that of HQ and the redox reaction of AMP is as reversible as that of HQ, resulting in a lower detection limit in a sandwich-type immunoassay using AMP for thyroid-stimulating hormone detection. The calculated detection limit is ~0.2 pg/mL. The use of AMP as an HRP substrate is especially promising for highly sensitive electrochemical immunoassays.

Ultrasensitive Detection of Parathyroid Hormone through Fast Silver Deposition Induced by Enzymatic Nitroso Reduction and Redox Cycling.

Enzymatically induced silver deposition and subsequent electrochemical oxidation have been widely used in electrochemical biosensors. However, this method is ineffective for producing highly enhanced silver deposition for use in ultrasensitive detection. Herein, we report a fast silver deposition method that simultaneously uses three signal amplification processes: (i) enzymatic amplification, (ii) chemical-chemical (CC) redox cycling, and (iii) chemical-enzymatic (CN) redox cycling. DT-diaphorase (DT-D) is used for enzymatic amplification to convert a nitroso compound, a species incapable of directly reducing Ag+ to an amine compound, which can directly reduce Ag+. NADH acts as a reducing agent for the indirect reduction of Ag+ via the two redox cycling processes. 4-Nitroso-1-naphthol is converted to 4-amino-1-naphthol (NH2-N) in the presence of DT-D. NH2-N initiates two redox cycling processes: NH2-N, along with Ag+ and NADH, are involved in the CC redox cycling, whereas NH2-N, along with Ag+, DT-D, and NADH, are involved in the CN redox cycling. Finally, the deposited silver is electrochemically oxidized to produce a signal. When this triple signal amplification strategy for fast silver deposition is applied to an electrochemical immunosensor for detecting parathyroid hormone (PTH), a detection limit as low as ∼100 fg/mL is obtained. The concentrations of PTH in clinical serum determined using the developed immunosensor are found to agree with those measured using a commercial instrument. Thus, the use of this strategy for fast silver deposition is highly promising for ultrasensitive electrochemical detection and biosensing applications.

Antioxidant therapy as monotherapy or as an adjunct to treatment of periodontal diseases.

BACKGROUND: Treatment of periodontal diseases by nonsurgical debridement has been considered as a gold standard procedure. Various other treatment modalities have been tried and tested to treat periodontal diseases. The aim of this study was to investigate the effect of antioxidant therapy on the progression of periodontal disease as monotherapy and/or as an adjunct to nonsurgical debridement. MATERIALS AND METHODS: 70 subjects were divided into three groups, i.e. clinically healthy, gingivitis and periodontitis group on the basis of Community Periodontal Index of Treatment Needs score. Gingivitis and periodontitis groups were further subdivided into three subgroups. At the baseline, periodontal attachment loss was recorded and scaling and root planing was performed in two subgroups. 6 mg antioxidant was administered in three divided doses for 2 weeks. Saliva samples were collected at baseline, 15(th) day, 30(th) day and 45(th) day for evaluation of uric acid levels. RESULTS: Uric acid levels were significantly low in patients with more periodontal attachment loss as compared to clinically healthy and gingivitis groups. As the treatment was initiated, significant increase in uric acid levels was observed. CONCLUSION: Rise in salivary antioxidant levels was observed on the administration of antioxidant therapy. Hence, antioxidant therapy can be used as an adjunct to the nonsurgical periodontal therapy.

Interleukin-6 promoter polymorphism (-174 G/C) in Indian patients with chronic periodontitis.

Recent studies have focused on genetic polymorphism of the interleukin-6 (IL-6) gene, which has led to a better understanding of the intricate interactions between host response, microorganisms, and genetics. Genotype prevalence appears to vary by the race and ethnicity of the population studied. We used a polymerase chain reaction technique to determine the prevalence of single nucleotide polymorphism in IL-6 at position -174 G>C in a population of 30 South Indians. Blood samples were collected from 15 chronic periodontitis patients and 15 healthy controls. The results showed that the G/G genotype was significantly more frequent in the chronic periodontitis group and that the C/C genotype was significantly more frequent in the control group (P = 0.0069 for both). The G allele was more frequent in chronic periodontitis patients (76.67%), whereas the C allele was more frequent in the control group (73.33%). Among chronic periodontitis patients, the odds ratio for having the G allele, as compared with the controls, was 9.04. In this population, the presence of the G/G genotype of IL-6 (-174) might increase susceptibility to chronic periodontitis, whereas the C/C genotype may have a protective effect.