Soft Bioelectronics Based on Nanomaterials.

Recent advances in nanostructured materials and unconventional device designs have transformed the bioelectronics from a rigid and bulky form into a soft and ultrathin form and brought enormous advantages to the bioelectronics. For example, mechanical deformability of the soft bioelectronics and thus its conformal contact onto soft curved organs such as brain, heart, and skin have allowed researchers to measure high-quality biosignals, deliver real-time feedback treatments, and lower long-term side-effects in vivo. Here, we review various materials, fabrication methods, and device strategies for flexible and stretchable electronics, especially focusing on soft biointegrated electronics using nanomaterials and their composites. First, we summarize top-down material processing and bottom-up synthesis methods of various nanomaterials. Next, we discuss state-of-the-art technologies for intrinsically stretchable nanocomposites composed of nanostructured materials incorporated in elastomers or hydrogels. We also briefly discuss unconventional device design strategies for soft bioelectronics. Then individual device components for soft bioelectronics, such as biosensing, data storage, display, therapeutic stimulation, and power supply devices, are introduced. Afterward, representative application examples of the soft bioelectronics are described. A brief summary with a discussion on remaining challenges concludes the review.

Chronic and acute stress monitoring by electrophysiological signals from adrenal gland.

We present electrophysiological (EP) signals correlated with cellular cell activities in the adrenal cortex and medulla using an adrenal gland implantable flexible EP probe. With such a probe, we could observe the EP signals from the adrenal cortex and medulla in response to various stress stimuli, such as enhanced hormone activity with adrenocorticotropic hormone, a biomarker for chronic stress response, and an actual stress environment, like a forced swimming test. This technique could be useful to continuously monitor the elevation of cortisol level, a useful indicator of chronic stress that potentially causes various diseases.

Experience With and Awareness of Telemedicine Among Korean Outpatients During the COVID-19 Pandemic.

Introduction: Owing to the coronavirus disease 19 pandemic, the demand for telemedicine has increased. However, the awareness of and experience with telemedicine among the Korean population have not been investigated. Therefore, we examined Korean outpatients' experience with and awareness of telemedicine. Methods: From December 2020 to March 2021, we conducted a survey exploring the awareness of and experience with telemedicine of outpatients who were consecutively enrolled by family physicians from four hospitals. The participants completed questionnaires on sociodemographic characteristics and knowledge, experience, satisfaction, preference, and future considerations concerning telemedicine. We evaluated factors associated with satisfaction with telemedicine experiences using multivariate logistic regression analysis. Results: Among the 563 study participants, 364 participants had experience with telemedicine. More than 95% of the telemedicine visits were performed by telephone consultation, and the most common disease type for telemedicine visits was chronic diseases (67.5%). Overall, 82.4% of the participants were satisfied with telemedicine. More than 90% of the participants were satisfied with telemedicine in terms of saving time and money relative to hospital visits, no risk of infection, and convenience. According to the multivariate logistic regression analysis, adults aged ≥65 years (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.44-8.68), residents of a metropolitan city (OR 6.8, 95% CI 1.41-32.55), and those with knowledge of telemedicine (OR 2.96, 95% CI 1.21-7.26) were more likely to be satisfied with their telemedicine experience, compared with their counterparts. For chronic diseases, participants with telemedicine experience were significantly more likely to prefer telemedicine for revisits, compared with those with no telemedicine experience. Nonetheless, most respondents recognized that telemedicine requires improvement. Conclusions: Most Korean outpatients showed high satisfaction with telemedicine. Telemedicine may be considered in various medical situations in the future. Therefore, building a practical system for telemedicine and changes in the medical environment are required.

Material Design and Fabrication Strategies for Stretchable Metallic Nanocomposites.

Stretchable conductive nanocomposites fabricated by integrating metallic nanomaterials with elastomers have become a vital component of human-friendly electronics, such as wearable and implantable devices, due to their unconventional electrical and mechanical characteristics. Understanding the detailed material design and fabrication strategies to improve the conductivity and stretchability of the nanocomposites is therefore important. This Review discusses the recent technological advances toward high performance stretchable metallic nanocomposites. First, the effect of the filler material design on the conductivity is briefly discussed, followed by various nanocomposite fabrication techniques to achieve high conductivity. Methods for maintaining the initial conductivity over a long period of time are also summarized. Then, strategies on controlled percolation of nanomaterials are highlighted, followed by a discussion regarding the effects of the morphology of the nanocomposite and postfabricated 3D structures on achieving high stretchability. Finally, representative examples of applications of such nanocomposites in biointegrated electronics are provided. A brief outlook concludes this Review.

Biosafe, Eco-Friendly Levan Polysaccharide toward Transient Electronics.

New options in the material context of transient electronics are essential to create or expand potential applications and to progress in the face of technological challenges. A soft, transparent, and cost-effective polymer of levan polysaccharide that is capable of complete, programmable dissolution is described when immersed in water and implanted in an animal model. The results include chemical analysis, the kinetics of hydrolysis, and adjustable dissolution rates of levan, and a simple theoretical model of reactive diffusion governed by temperature. In vivo experiments of the levan represent nontoxicity and biocompatibility without any adverse reactions. On-demand, selective control of dissolution behaviors with an animal model demonstrates an effective triggering strategy to program the system's lifetime, providing the possibility of potential applications in envisioned areas such as bioresorbable electronic implants and drug release systems.

Risk of osteoporosis after gastrectomy in long-term gastric cancer survivors.

INTRODUCTION: Although early detection and successful gastrectomy have improved the survival of patients with gastric cancer, long-term health problems remain troubling. We evaluated the prevalence of osteoporosis and its risk factors in long-term survivors of gastric cancer after gastrectomy. METHODS: We reviewed the medical records of a tertiary hospital between 2007 and 2014 to identify survivors of gastric cancer who had visited our center at around 5 years after gastrectomy. We evaluated their health status, including bone mineral density (BMD). Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and femur (total and neck area). The prevalence of osteoporosis, defined by a BMD T score <-2.5, was investigated, and clinical variables associated with the presence of osteoporosis were identified. RESULTS: A total of 250 survivors were included. The mean age was 54.6 years old, and the median follow-up was 6.0 years. The prevalence of osteoporosis was 34.0% (27.4% for men and 43.6% for women). Older age [odds ratio (OR) 5.50, 95% CI 2.33-13.00], higher alkaline phosphatase levels before gastrectomy (OR 5.67, 95% CI 1.36-23.64), and marked weight loss (≥20%) after gastrectomy (OR 3.59, 95% CI 1.32-9.77) were independently associated with the presence of osteoporosis. CONCLUSIONS: In our cohort, osteoporosis was commonly observed in long-term survivors of gastric cancer, and several risk factors for it were identified. To reduce the risk of osteoporosis after gastrectomy, maintaining adequate body weight may be necessary.

The Effect of Sleep Quality on the Development of Type 2 Diabetes in Primary Care Patients.

Sleep has important effects on physical and mental health, and sleep disorders are associated with increased mortality and morbidity. This study was conducted to evaluate the relationship between sleep duration or sleep quality and the risk of type 2 diabetes. The FACTS (FAmily CohorT Study in primary care) was established to investigate the relations between familial environment and health which was conducted at 22 family medicine outpatient clinics in general hospitals. Total 563 patients without diabetes who received ≥1 year follow-up examination were included in the analysis. We used the Pittsburgh Sleep Quality Index to determine sleep quality, and a score of ≥5 was considered to define poor sleep quality. Patients taking oral hypoglycemic agents, having a fasting glucose level of >126 mg/dL, or diagnosed with diabetes by physicians were classified as having diabetes. The median follow-up period was 2.5 years. Poor sleep quality was associated with a higher risk of diabetes after adjusting for age, sex, body mass index, income, physical activity, and family history of diabetes (relative risk=2.64; 95% confidence interval, 1.03-6.78). As a risk factor for the development of diabetes, poor sleep quality may independently increase the incidence of diabetes.

Association Between the Number of Chronic Diseases and Oral Health Problems in Korean Adults.

PURPOSE: The relationship between the number of chronic diseases and oral health problems is unclear. We sought to determine whether the number of chronic diseases and multimorbidity have an association with oral health problems in Korean adults. MATERIALS AND METHODS: Data from 23,246 adults aged ≥ 19 years, who participated in the Korea National Health and Nutrition Examination Survey from 2016 to 2019, were considered for our analyses. Participants with either masticatory or speech problems were defined as the oral health problems group. Individuals who reported having had dental treatment in the last year were defined as the dental treatment group. We used multivariable logistic regression analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The proportions of oral health problems and dental treatment were higher in participants with multimorbidity than in those without multimorbidity (all p < 0.001). Moreover, ORs of oral health problems demonstrated a tendency to increase with the number of chronic diseases, even after adjustment (p for trend < 0.001). Compared to the participants without multimorbidity, the risk of having oral health problems increased by 25% (OR: 1.25, 95% CI: 1.12-1.39), and that of receiving dental treatment increased by 23% (OR: 1.23, 95% CI: 1.13-1.34) in patients with multimorbidity. CONCLUSION: The risk of oral health problems and dental treatment increased in association with the number of chronic diseases in Korean adults. The authors emphasise the risks and importance of oral health in a large population affected by multiple chronic diseases.

Relationship between visit-to-visit blood pressure variability and depressive mood in Korean primary care patients.

BACKGROUND: High blood pressure variability (BPV) increases the risk of cardiovascular disease and may be better prognostic factor than blood pressure. Depressive mood is a common symptom among patients visiting primary care. This study aimed to investigate the association between depressive mood and high BPV among Korean primary care patients. METHODS: The Family Cohort Study in Primary Care (FACTS), conducted from April 2009 to November 2017, utilized a prospective cohort of Korean primary care patients, with a median follow-up period of 7.25 years. Depressive mood was assessed as a score of 21 points or more on the Korean-type Center for Epidemiologic Studies Depression scale. BP was measured at the initial visit and first and second follow-up visit. Visit-to visit SBP variability was analyzed using four metrics: intra-individual standard deviation, coefficient of variation, variation independent of mean, and average real variability. Logistic regression analysis was used to estimate the association of high BPV with depressive mood and other variables. RESULTS: Among 371 participants, 43 (11.6%) had depressive mood based on depression scores. Older age (odds ratio [OR]: 1.04, 95% confidence interval [CI]: 1.01-1.07) were associated with high SBP variability regardless of taking antihypertensive medication. Among participants taking antihypertensive medication, those with depressive mood had twice the risk of high SBP variability compared with those who did not (OR: 2.95, 95% CI: 1.06-8.20). CONCLUSIONS: Depressive mood was associated with high visit-to-visit SBP variability in primary care patients taking antihypertensive medication, potentially indicating increased cardiovascular risk. Primary care physicians should therefore closely monitor BPV in patients with depressive symptoms and provide appropriate interventions.

Next-Generation Cardiac Interfacing Technologies Using Nanomaterial-Based Soft Bioelectronics.

Cardiac interfacing devices are essential components for the management of cardiovascular diseases, particularly in terms of electrophysiological monitoring and implementation of therapies. However, conventional cardiac devices are typically composed of rigid and bulky materials and thus pose significant challenges for effective long-term interfacing with the curvilinear surface of a dynamically beating heart. In this regard, the recent development of intrinsically soft bioelectronic devices using nanocomposites, which are fabricated by blending conductive nanofillers in polymeric and elastomeric matrices, has shown great promise. The intrinsically soft bioelectronics not only endure the dynamic beating motion of the heart and maintain stable performance but also enable conformal, reliable, and large-area interfacing with the target cardiac tissue, allowing for high-quality electrophysiological mapping, feedback electrical stimulations, and even mechanical assistance. Here, we explore next-generation cardiac interfacing strategies based on soft bioelectronic devices that utilize elastic conductive nanocomposites. We first discuss the conventional cardiac devices used to manage cardiovascular diseases and explain their undesired limitations. Then, we introduce intrinsically soft polymeric materials and mechanical restraint devices utilizing soft polymeric materials. After the discussion of the fabrication and functionalization of conductive nanomaterials, the introduction of intrinsically soft bioelectronics using nanocomposites and their application to cardiac monitoring and feedback therapy follow. Finally, comments on the future prospects of soft bioelectronics for cardiac interfacing technologies are discussed.

Low-impedance tissue-device interface using homogeneously conductive hydrogels chemically bonded to stretchable bioelectronics.

Stretchable bioelectronics has notably contributed to the advancement of continuous health monitoring and point-of-care type health care. However, microscale nonconformal contact and locally dehydrated interface limit performance, especially in dynamic environments. Therefore, hydrogels can be a promising interfacial material for the stretchable bioelectronics due to their unique advantages including tissue-like softness, water-rich property, and biocompatibility. However, there are still practical challenges in terms of their electrical performance, material homogeneity, and monolithic integration with stretchable devices. Here, we report the synthesis of a homogeneously conductive polyacrylamide hydrogel with an exceptionally low impedance (~21 ohms) and a reasonably high conductivity (~24 S/cm) by incorporating polyaniline-decorated poly(3,4-ethylenedioxythiophene:polystyrene). We also establish robust adhesion (interfacial toughness: ~296.7 J/m2) and reliable integration between the conductive hydrogel and the stretchable device through on-device polymerization as well as covalent and hydrogen bonding. These strategies enable the fabrication of a stretchable multichannel sensor array for the high-quality on-skin impedance and pH measurements under in vitro and in vivo circumstances.

Highly Conductive and Stretchable Hydrogel Nanocomposite Using Whiskered Gold Nanosheets for Soft Bioelectronics.

The low electrical conductivity of conductive hydrogels limits their applications as soft conductors in bioelectronics. This low conductivity originates from the high water content of hydrogels, which impedes facile carrier transport between conductive fillers. This study presents a highly conductive and stretchable hydrogel nanocomposite comprising whiskered gold nanosheets. A dry network of whiskered gold nanosheets is fabricated and then incorporated into the wet hydrogel matrices. The whiskered gold nanosheets preserve their tight interconnection in hydrogels despite the high water content, providing a high-quality percolation network even under stretched states. Regardless of the type of hydrogel matrix, the gold-hydrogel nanocomposites exhibit a conductivity of ≈520 S cm-1 and a stretchability of ≈300% without requiring a dehydration process. The conductivity reaches a maximum of ≈3304 S cm-1 when the density of the dry gold network is controlled. A gold-adhesive hydrogel nanocomposite, which can achieve conformal adhesion to moving organ surfaces, is fabricated for bioelectronics demonstrations. The adhesive hydrogel electrode outperforms elastomer-based electrodes in in vivo epicardial electrogram recording, epicardial pacing, and sciatic nerve stimulation.

Needle-Like Multifunctional Biphasic Microfiber for Minimally Invasive Implantable Bioelectronics.

Implantable bioelectronics has attracted significant attention in electroceuticals and clinical medicine for precise diagnosis and efficient treatment of target diseases. However, conventional rigid implantable devices face challenges such as poor tissue-device interface and unavoidable tissue damage during surgical implantation. Despite continuous efforts to utilize various soft materials to address such issues, their practical applications remain limited. Here, a needle-like stretchable microfiber composed of a phase-convertible liquid metal (LM) core and a multifunctional nanocomposite shell for minimally invasive soft bioelectronics is reported. The sharp tapered microfiber can be stiffened by freezing akin to a conventional needle to penetrate soft tissue with minimal incision. Once implanted in vivo where the LM melts, unlike conventional stiff needles, it regains soft mechanical properties, which facilitate a seamless tissue-device interface. The nanocomposite incorporating with functional nanomaterials exhibits both low impedance and the ability to detect physiological pH, providing biosensing and stimulation capabilities. The fluidic LM embedded in the nanocomposite shell enables high stretchability and strain-insensitive electrical properties. This multifunctional biphasic microfiber conforms to the surfaces of the stomach, muscle, and heart, offering a promising approach for electrophysiological recording, pH sensing, electrical stimulation, and radiofrequency ablation in vivo.

Floatable photocatalytic hydrogel nanocomposites for large-scale solar hydrogen production.

Storing solar energy in chemical bonds aided by heterogeneous photocatalysis is desirable for sustainable energy conversion. Despite recent progress in designing highly active photocatalysts, inefficient solar energy and mass transfer, the instability of catalysts and reverse reactions impede their practical large-scale applications. Here we tackle these challenges by designing a floatable photocatalytic platform constructed from porous elastomer-hydrogel nanocomposites. The nanocomposites at the air-water interface feature efficient light delivery, facile supply of water and instantaneous gas separation. Consequently, a high hydrogen evolution rate of 163 mmol h-1 m-2 can be achieved using Pt/TiO2 cryoaerogel, even without forced convection. When fabricated in an area of 1 m2 and incorporated with economically feasible single-atom Cu/TiO2 photocatalysts, the nanocomposites produce 79.2 ml of hydrogen per day under natural sunlight. Furthermore, long-term stable hydrogen production in seawater and highly turbid water and photoreforming of polyethylene terephthalate demonstrate the potential of the nanocomposites as a commercially viable photocatalytic system.

Minimally-Invasive and In-Vivo Hydrogel Patterning Method for In Situ Fabrication of Implantable Hydrogel Devices.

Despite advances in a wide range of device applications of hydrogels, including implantable ones, a method for deploying patterned hydrogel devices into the body in a minimally-invasive manner is not available yet. However, in situ patterning of the hydrogel in vivo has an obvious advantage, by which incision surgery for implantation of the hydrogel device can be avoided. Here, a minimally-invasive and in vivo hydrogel patterning method for in situ fabrication of implantable hydrogel devices is presented. The sequential application of injectable hydrogels and enzymes, with assistance of minimally-invasive surgical instruments, enables the in vivo and in situ hydrogel patterning. This patterning method can be achieved by adopting an appropriate combination of the sacrificial mold hydrogel and the frame hydrogel, in consideration of unique material properties of the hydrogels such as high softness, facile mass transfer, biocompatibility, and diverse crosslinking mechanisms. In vivo and in situ patterning of the hydrogels functionalized with nanomaterials is also demonstrated to fabricate the wireless heater and tissue scaffold, showcasing broad applicability of the patterning method.

Stretchable Low-Impedance Conductor with Ag-Au-Pt Core-Shell-Shell Nanowires and in Situ Formed Pt Nanoparticles for Wearable and Implantable Device.

Mechanically soft metallic nanocomposites have gained much attention as a key material for intrinsically stretchable biointegrated devices. However, it has been challenging to develop a stretchable conductive nanocomposite with all the desired material characteristics including high conductivity, high stretchability, low cytotoxicity, and low impedance. Here, we present a material strategy for the stretchable conductive nanocomposite, particularly emphasizing low impedance, by combining silver-gold-platinum core-shell-shell nanowires and homogeneously dispersed in situ synthesized platinum nanoparticles (Pt NPs). The highly embossed structure of the outermost Pt shell, together with the intrinsic electrical property of Pt, contributes to minimizing the impedance. The gold-platinum double-layer sheath prevents leaching of cytotoxic Ag ions, thus improving biocompatibility. Homogeneously dispersed Pt NPs, synthesized in situ during fabrication of the nanocomposite, simultaneously enhance conductivity, reduce impedance, and improve stretchability by supporting the percolation network formation. This intrinsically stretchable nanocomposite conductor can be applied to wearable and implantable bioelectronics for recording biosignals and delivering electrical stimulations in vivo.

Ventricular tachyarrhythmia treatment and prevention by subthreshold stimulation with stretchable epicardial multichannel electrode array.

The implantable cardioverter-defibrillator (ICD) is an effective method to prevent sudden cardiac death in high-risk patients. However, the transvenous lead is incompatible with large-area electrophysiological mapping and cannot accommodate selective multichannel precision stimulations. Moreover, it involves high-energy shocks, resulting in pain, myocardial damage, and recurrences of ventricular tachyarrhythmia (VTA). We present a method for VTA treatment based on subthreshold electrical stimulations using a stretchable epicardial multichannel electrode array, which does not disturb the normal contraction or electrical propagation of the ventricle. In rabbit models with myocardial infarction, the infarction was detected by mapping intracardiac electrograms with the stretchable epicardial multichannel electrode array. Then, VTAs could be terminated by sequential electrical stimuli from the epicardial multichannel electrode array beginning with low-energy subthreshold stimulations. Last, we used these subthreshold stimulations to prevent the occurrence of additional VTAs. The proposed protocol using the stretchable epicardial multichannel electrode array provides opportunities toward the development of innovative methods for painless ICD therapy.

Highly Efficient Nitrogen-Fixing Microbial Hydrogel Device for Sustainable Solar Hydrogen Production.

Conversion of sunlight and organic carbon substrates to sustainable energy sources through microbial metabolism has great potential for the renewable energy industry. Despite recent progress in microbial photosynthesis, the development of microbial platforms that warrant efficient and scalable fuel production remains in its infancy. Efficient transfer and retrieval of gaseous reactants and products to and from microbes are particular hurdles. Here, inspired by water lily leaves floating on water, a microbial device designed to operate at the air-water interface and facilitate concomitant supply of gaseous reactants, smooth capture of gaseous products, and efficient sunlight delivery is presented. The floatable device carrying Rhodopseudomonas parapalustris, of which nitrogen fixation activity is first determined through this study, exhibits a hydrogen production rate of 104 mmol h-1  m-2 , which is 53 times higher than that of a conventional device placed at a depth of 2 cm in the medium. Furthermore, a scaled-up device with an area of 144 cm2 generates hydrogen at a high rate of 1.52 L h-1  m-2 . Efficient nitrogen fixation and hydrogen generation, low fabrication cost, and mechanical durability corroborate the potential of the floatable microbial device toward practical and sustainable solar energy conversion.

Facile and Scalable Synthesis of Whiskered Gold Nanosheets for Stretchable, Conductive, and Biocompatible Nanocomposites.

Noble metal nanomaterials have been studied as conductive fillers for stretchable, conductive, and biocompatible nanocomposites. However, their performance as conductive filler materials is far from ideal because of their high percolation threshold and low intrinsic conductivity. Moreover, the difficulty in large-scale production is another critical hurdle in their practical applications. Here we report a method for the facile and scalable synthesis of whiskered gold nanosheets (W-AuNSs) for stretchable, conductive, and biocompatible nanocomposites and their application to stretchable bioelectrodes. W-AuNSs show a lower percolation threshold (1.56 vol %) than those of gold nanoparticles (5.02 vol %) and gold nanosheets (2.74 vol %), which enables the fabrication of W-AuNS-based stretchable nanocomposites with superior conductivity and high stretchability. Addition of platinum-coated W-AuNSs (W-AuNSs@Pt) to the prepared nanocomposite significantly reduces the impedance and improved charge storage capacity. Such enhanced performance of the stretchable nanocomposite enables us to fabricate stretchable bioelectrodes whose performance is demonstrated through animal experiments including electrophysiological recording and electrical stimulation in vivo.

Multifunctional Injectable Hydrogel for In Vivo Diagnostic and Therapeutic Applications.

Injectable hydrogels show high potential for in vivo biomedical applications owing to their distinctive mode of administration into the human body. In this study, we propose a material design strategy for developing a multifunctional injectable hydrogel with good adhesiveness, stretchability, and bioresorbability. Its multifunctionality, whereupon multiple reactions occur simultaneously during its injection into the body without requiring energy stimuli and/or additives, was realized through meticulous engineering of bioresorbable precursors based on hydrogel chemistry. The multifunctional injectable hydrogel can be administered through a minimally invasive procedure, form a conformal adhesive interface with the target tissue, dynamically stretch along with the organ motions with minimal mechanical constraints, and be resorbed in vivo after a specific period. Further, the incorporation of functional nanomaterials into the hydrogel allows for various in vivo diagnostic and therapeutic applications, without compromising the original multifunctionality of the hydrogel. These features are verified through theranostic case studies on representative organs, including the skin, liver, heart, and bladder.